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JP4103147B2 - Benzamidine derivatives - Google Patents
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JP4103147B2 - Benzamidine derivatives - Google Patents

Benzamidine derivatives Download PDF

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Publication number
JP4103147B2
JP4103147B2 JP53411798A JP53411798A JP4103147B2 JP 4103147 B2 JP4103147 B2 JP 4103147B2 JP 53411798 A JP53411798 A JP 53411798A JP 53411798 A JP53411798 A JP 53411798A JP 4103147 B2 JP4103147 B2 JP 4103147B2
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group
carbon atoms
mmol
formula
yield
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JPWO1998031661A1 (en
Inventor
大 高柳
和之 鷺
忠清 中川
雅博 山梨
孝志 栢原
俊二 竹花
弓子 福田
三雄 高橋
政孝 東海林
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D209/04—Indoles; Hydrogenated indoles
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Manufacture Of Alloys Or Alloy Compounds (AREA)

Abstract

Benzamidine derivatives of the following formulae or analogs thereof, i. e., pharmaceutically acceptable salts thereof, are provided. These compounds or salts thereof have a blood-coagulation inhibiting effect based on an excellent effect of inhibiting the action of activated blood coagulation factor X, and they are useful as anticoagulants. <CHEM>

Description

発明の背景
本発明は活性化血液凝固第Ｘ因子を可逆的に阻害して強力な抗凝固作用を示す経口投与可能な新規ベンズアミジン誘導体及びそれらを有効成分として含有する血液凝固抑制剤または血栓若しくは塞栓によって引き起こされる疾病の予防・治療剤に関するものである。適応する前記疾病として例えば脳梗塞、脳血栓、脳塞栓、一過性脳虚血発作（ＴＩＡ）、くも膜下出血（血管れん縮）等の脳血管障害における疾病、急性及び慢性心筋梗塞、不安定狭心症、冠動脈血栓溶解等の虚血性心疾患における疾病、肺梗塞、肺塞栓等の肺血管障害における疾病、末梢動脈閉塞症、深部静脈血栓症、汎発性血管内凝固症候群、さらに人工血管術及び人工弁置換後の血栓形成、冠動脈バイパス術後における再閉塞及び再狭窄、経皮的経管式冠動脈形成術（ＰＴＣＡ）または経皮的経管式冠動脈再開通療法（ＰＴＣＲ）等の血行再建後の再閉塞及び再狭窄、体外循環時の血栓形成などが挙げられる。
生活習慣の欧米化、人口の高齢化などに伴い、心筋梗塞、脳血栓症、末梢動脈血栓症をはじめとする血栓塞栓性疾患は年々増加する傾向にあり、その治療の社会的重要性はますます高まっている。抗血液凝固療法は、線溶療法及び抗血小板療法とともに血栓症の治療及び予防における内科的治療法の一端を担っている。
従来、血栓形成抑制剤として抗トロンビン剤の開発が行われてきたが、トロンビンは凝固反応の最終段階であるフィブリノーゲンのフィブリンへの活性化を司るばかりでなく、血小板の活性化及び凝集にも深く関与していることから、その阻害は出血傾向をきたす危険のあることが知られていた。また、経口投与でのbioavailabilityが低く、現在のところ経口投与可能なトロンビン阻害剤は上市されていない。
活性化血液凝固第Ｘ因子は外因系及び内因系凝固カスケード反応の合流点に位置し、トロンビンよりも上流に位置するため、本因子の阻害はトロンビン阻害よりも効率的にかつ、特異的に凝固系を阻害できる可能性がある［トロンボシスリサーチ（THROMBOSIS RESEARCH）１９巻、３３９−３４９ページ、１９８０年］。
発明の開示
本発明は優れた活性化血液凝固第Ｘ因子阻害作用を有する化合物を提供することにある。
本発明は経口投与可能な活性化血液凝固第Ｘ因子に特異的な阻害作用を有する化合物を提供することにある。
本発明は上記化合物を含有する抗血液凝固剤または血栓もしくは塞栓の予防・治療剤を提供することにある。
本発明者らは、前記実状を鑑み、種々研究を行った結果、ある特定の新規ベンズアミジン誘導体が優れた活性化血液凝固第Ｘ因子阻害作用を有することを示し、血栓・塞栓に基づく種々の疾病の予防並びに治療薬として有用であることを見いだし、本発明を完成させるに到った。すなわち本発明は、下記一般式（１）で示されるベンズアミジン誘導体またはその医薬的に許容しうる塩、並びにそれらを有効成分とする抗血液凝固剤である。

Figure 0004103147
［一般式（１）中、Ｌは下式（２）から（５）のいずれかの有機基を示す。
Figure 0004103147
（式（２）、（３）、（５）中、Ｗは、水素原子、炭素数１〜６のアルキル基、炭素数４〜１０のアリール基、炭素数５〜１２のアラルキル基もしくは炭素数２〜４のカルボキシルアルキルスルホニル基を示し、式（３）中、Ｄ又はＤ′のいづれか一方が一般式（１）中のＹとの結合を示し、もう一方が水素原子を示し、
式（２）中、Ｘは、水素原子、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基または置換基を有していてもよいメチル、エチルもしくはベンジル基を示し、置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜１０のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、アミジノピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、アミジノ基、ヒドロキシ基、ハロゲノ基、インドリル基もしくは炭素数１〜５のアルキル基があげられる。また式（２）中、ＸとＷは結合して環を構成してもよく、この場合−Ｗ−Ｘ−はエチレン基、トリメチレン基もしくはテトラメチレン基を示す。）
Ｌが式（２）または（３）のいずれかの有機基の場合、Ｖは、水素原子、置換基を有するフェニル又はベンゾイル基、置換基を有していてもよいベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、ピリジンカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示す。
Ｌが式（４）の有機基の場合、Ｖは、置換基を有するベンゾイル基、置換基を有していてもよい２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示す。Ｌが式（５）の有機基の場合、Ｖは置換基を有していても良い炭素数４から１０のアリール基を示す。
Ｌが式（２）〜（５）のいずれかの有機基の場合において、Ｖが置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数１〜３のアルコキシ基で置換されてもよい炭素数１〜８のアシル基、ハロゲノ基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数２〜７のアルコキシカルボニルアミノ基、炭素数１〜３のアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、アミノ基で置換されてもよい炭素数６〜９のアシルピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数２〜７のヒドロキシカルボニルアルキル基、炭素数３〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数１〜１０のアルコキシ基、ニトロ基、トリフルオロメチル基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数５〜１２のアリールアルキル基、ピペラジンカルボニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、ベンジルスルホニルアミノ基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペリジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、アミノエチルオキシ基、炭素数３〜６のジアルキルアミノスルホニル基、炭素数２〜４のジアルキルグアジニノ基が挙げられる。
Ｌが式（２）〜（４）のいずれかの有機基の場合には、或いはＶは次の式（６）の有機基を示す。
Figure 0004103147
（Ｒ1は水素原子、アルコキシカルボニル基もしくはメチル基のいずれかを表し、Ｒ2は水素原子、メチル基、ブチル基、ベンジル基、アミノブチル基、ヒドロキシカルボニルエチル基、ヒドロキシカルボニルプロピル基もしくはイミダゾリルメチル基のいずれかを表し、Ｒ3は水素原子もしくはピリジル基を示す。）
Ｙは下式（７）、（８）、（９）、（１０）または（１１）のいずれかを示す。
Figure 0004103147
（式（７）および（８）中、ｎは１〜３の整数を示す。）
Ｚは水素原子、炭素数１〜６のアルキル基、ハロゲノ基または下式（１２−１）、（１２−２）、（１２−３）のいずれかを示す。
Figure 0004103147
（Ｒ4はカルボキシル基もしくは炭素数４〜１０のアリール基のいずれか、Ｒ5は炭素数１〜６のアルキル基、Ｒ6は水素原子、炭素数１〜６のアルキル基又は炭素数１〜７のアルコキシ基のいずれか、Ｒ7は水素原子又は炭素数１〜６のアルキル基のいずれかを示す。）］
発明を実施するための最良の形態
一般式（１）の化合物としては、下記の化合物が好ましい。
一般式（１）中、Ｌが式（２）から（５）のいずれかの有機基を示し、式（２）中、Ｗが、水素原子、炭素数１〜６のアルキル基、炭素数４〜１０のアリール基もしくは炭素数５〜１２のアラルキル基を示し、式（３）及び（５）中、Ｗは水素原子を示し、式（３）中、Ｄが一般式（１）中のＹとの結合を示し、Ｄ′が水素原子を示し、
Ｘが、水素原子、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基または置換基を有していてもよいメチル、エチルもしくはベンジル基を示し、置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、アミジノ基、ヒドロキシ基、ハロゲノ基、インドリル基もしくは炭素数１〜３のアルキル基があげられ、また式（２）中、ＸとＷは結合して環を構成してもよく、この場合−Ｗ−Ｘ−はエチレン基、トリメチレン基もしくはテトラメチレン基を示し、
Ｌが式（２）または（３）のいずれかの有機基の場合、Ｖは、水素原子、置換基を有するベンゾイル基、置換基を有していてもよいベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示し、
Ｌが式（４）の有機基の場合、Ｖは、置換基を有するベンゾイル基、置換基を有していてもよい２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示し、Ｌが式（５）の有機基の場合、Ｖは置換基を有していても良い炭素数４から１０のアリール基を示し、
Ｌが式（２）〜（５）のいずれかの有機基の場合において、Ｖが置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数１〜８のアシル基、ハロゲノ基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数２〜７のアルコキシカルボニルアミノ基、炭素数１〜３のアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数３〜７のヒドロキシカルボニルアルキル基、炭素数４〜８のアルコキシカルボニルアルキル基、炭素数２〜７のヒドロキシカルボニルアルケニル基、炭素数３〜８のアルコキシカルボニルアルケニル基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数１〜１０のアルコキシ基、ニトロ基、トリフルオロメチル基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数５〜１２のアリールアルキル基、ピペラジンカルボニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、ベンジルスルホニルアミノ基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペリジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、アミノエチルオキシ基が挙げられ、
Ｌが式（２）〜（４）のいずれかの有機基の場合には、或いはＶは式（６）の有機基を示し、
Ｙが式（７）、（８）、（９）、（１０）または（１１）のいずれかを示し、式（７）中、ｎは１又は２であり、式（８）中、ｎは１であり、
Ｚが水素原子、炭素数１〜６のアルキル基、ハロゲノ基または式（１２−１）のいずれかを示し、式（１２−１）中、Ｒ4はカルボキシル基もしくは炭素数４〜１０のアリール基のいずれかを示す、ベンズアミジン誘導体またはその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｖが置換基を有する場合の置換基が、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、カルバモイル基、アミジノ基、アセチル基、臭素原子、アミノ基、メチルアミノ基、ｔ−ブトキシカルボニルアミノ基、アミノメチル基、（メチルアミノ）メチル基、（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、３−ピロリジルオキシ基、１−ｔ−ブトキシカルボニル−３−ピロリジルオキシ基、２−カルボキシルエテニル基、２−（エトキシカルボニル）エテニル基、ジメチルカルバモイル基、Ｎ−エチル−Ｎ−メチルカルバモイル基、２−イミダゾリニル基、１−ピペリジンカルボニル基、Ｎ，Ｎ−ジメチルアミジノ基、２−（テトラヒドロピリミジニル）基、１−ピロリジンカルボニル基、２−（４−ピリジル）ビニル基、１−ピロール基、シクロヘキシルオキシ基、ジエチルアミノ基、２−（４−ピリジル）エチル基、イソプロピル基、１−ピロリジル基、ベンゾイル基、ベンゼンスルホニル基、ベンジル基、４−ピリジル基、ジメチルアミノ基、１−ピペリジニル基、フェノキシ基、１−ピペラジンカルボニル基、１−アセトイミドイル−４−ピペラジンカルボニル基、（４−ピリジル）アミノ基、メチルカルバモイル基、フェニル基、シクロヘキシル基、１−ピペラジンスルホニル基、１−アセトイミドイル−４−ピペラジンスルホニル基、４−（ピリジル）メチル基、４−ピペリジリデンメチル基、４−ピペリジルメチル基、１−アセトイミドイル−４−ピペリジリデンメチル基、１−アセトイミドイル−４−ピペリジルメチル基、２−イミダゾリル基、１−フェノキシカルボニル−４−ピペリジルオキシ基、モノエトキシヒドロキシホスホリル基、ジエトキシホスホリル基、塩素原子、１−（アミノアセチル）−４−ピペリジルオキシ基、トリフルオロメチル基、ベンジルスルホニルアミノ基、グアニジノ基、ホスホノ基もしくはアミノエチルオキシ基のいずれかである、ベンズアミジン誘導体またはその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｗが、水素原子、メチル基もしくはベンジル基のいずれかである、ベンズアミジン誘導体またはその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｘが置換基を有する場合の置換基が、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、エタンスルホニルオキシ基、ブタンスルホニルオキシ基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、１−ベンジルオキシカルボニル−４−ピペリジルオキシ基、４−ピペリジルメチル基、（１−アセトイミドイル−４−ピペリジル）メチル基、１−アセトイミドイル−３−ピロリジルオキシ基、イソプロピル基、３−インドリル基もしくはヨウ素原子のいずれかである、ベンズアミジン誘導体またはその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｚが、水素原子、ヨウ素原子、メチル基、２−カルボキシル−２−オキソエチル基もしくは２−（２−フリル）−２−オキソエチル基のいずれかである、ベンズアミジン誘導体またはその医薬的に許容しうる塩が好ましい。
又は、一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗが、水素原子、炭素数１〜６のアルキル基、炭素数４〜１０のアリール基もしくは炭素数５〜１２のアラルキル基を示し、
Ｘが、水素原子、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基または置換基を有していてもよいメチル、エチルもしくはベンジル基を示し、置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基を示し、
Ｖが、水素原子、置換基を有するベンゾイル基、置換基を有していてもよいベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチルまたは置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示し、
Ｖが置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜３のアミノアルキル基、炭素数２〜７のアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数３〜７のヒドロキシカルボニルアルキル基、炭素数４〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基が挙げられ、
或いはＶは式（６）の有機基を示し、（式（６）中、Ｒ1は水素原子、アルコキシカルボニル基又はメチル基を表し、Ｒ2はメチル基、ブチル基、ベンジル基、アミノブチル基、ヒドロキシカルボニルエチル基、ヒドロキシカルボニルプロピル基もしくはイミダゾリルメチル基のいずれかを表し、Ｒ3は水素原子を示す。）、
Ｙが式（７）、（８）、（９）、（１０）または（１１）のいずれかを示し、式（７）中、ｎは１又は２であり、式（８）中、ｎは１であり、
Ｚが水素原子、炭素数１〜６のアルキル基、ハロゲノ基または式（１２−１）のいずれかを示し、式（１２−１）中、Ｒ4はカルボキシル基もしくは炭素数４〜１０のアリール基のいずれかを示す、ベンズアミジン誘導体またはその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｖが置換基を有する場合の置換基がカルボキシル基、メトキシカルボニル基、エトキシカルボニル基、アミノカルボニル基、アミジノ基、アセチル基、臭素原子、アミノ基、メチルアミノ基、ｔ−ブトキシカルボニルアミノ基、アミノメチル基、（メチルアミノ）メチル基、（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、３−ピロリジルオキシ基、１−ｔ−ブトキシカルボニル−３−ピロリジルオキシ基、２−カルボキシルエテニル基、２−（エトキシカルボニル）エテニル基のいずれかである、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｗが水素原子、メチル基、ベンジル基のいずれかである、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｘが置換基を有する場合の置換基がカルボキシル基、メトキシカルボニル基、エトキシカルボニル基、エタンスルフォニルオキシ基、ブタンスルフォニルオキシ基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、１−ベンジルオキシカルボニル−４−ピペリジルオキシ基、４−ピペリジルメチル基、（１−アセトイミドイル−４−ピペリジル）メチル基、１−アセトイミドイル−３−ピロリジルオキシ基のいずれかである、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｚが水素原子、ヨウ素原子、メチル基、２−カルボキシル２−オキソエチル基、２−（２−フリル）−２−オキソエチル基のいずれかである、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
又は、一般式（１）中、Ｌが式（２）又は式（４）の有機基を示し、式（２）中、Ｗが、水素原子又は炭素数１〜６のアルキル基を示し、
Ｘが、水素原子、炭素数２〜３のカルボキシアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数１〜８のアシル基、ハロゲノ基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数２〜７のアルコキシカルボニルアミノ基、炭素数１〜３のアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数２〜７のヒドロキシカルボニルアルキル基、炭素数３〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数１〜１０のアルコキシ基、ニトロ基、トリフルオロメチル基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数５〜１２のアリールアルキル基、ピペラジンカルボニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、ベンジルスルホニルアミノ基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペリジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、アミノエチルオキシ基、炭素数３〜６のジアルキルアミノスルホニル基、炭素数２〜４のジアルキルグアニジノ基が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが、水素原子、（１２-2-1）、（１２−３）のいずれかを示す、
Figure 0004103147
（Ｒ51は、水素原子または炭素数１〜６のアルキル基、Ｒ6は水素原子、炭素数１〜６のアルキル基又は炭素数１〜７のアルコキシ基のいずれか、Ｒ7は水素原子又は炭素数１〜６のアルキル基のいずれかを示す。）］
ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｌが式（２）の有機基を示す、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗが、水素原子又は炭素数１〜６のアルキル基を示し、
Ｘが、水素原子、炭素数２〜３のカルボキシアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数２〜８のアシル基、炭素数２〜６のジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数３〜７のジアルキルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数６〜１０のアルコキシ基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペリジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基が挙げらる、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗは、水素原子又はメチル基を示し、Ｘが、水素原子、炭素数２〜３のカルボキシルアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、１−（ピリジル）−ピペリジン−４−カルボニル基又は置換基を有するベンゾイル基を示し、該置換基としては炭素数３〜７のジアルキルカルバモイル基、炭素数３〜７のジアルキルアミジノ基、ベンゾイル基、炭素数２〜６のジアルキルアミノ基、ピリジルアミノ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数６〜７のピリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが水素原子、式（１２−２−１）を示す、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗは、水素原子を示し、Ｘが、水素原子、炭素数２〜３のカルボキシルアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、１−（４−ピリジル）−ピペリジン−４−カルボニル基又はパラ位に置換基を有するベンゾイル基を示し、該置換基としてはジメチルカルバモイル基、（ピロリジン−１−イル）カルボニル基、Ｎ，Ｎ−ジメチルアミジノ基、（ピロリジン−１−イル）（イミノ）メチル基、ベンゾイル基、１−ピロリジル基、４−ピリジルアミノ基、１−アセトイミドイル−４−ピペリジルオキシ基、４−ピリジルエチル基、グアニジノ基、が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが式（１２−２−１）を示す、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
又は、一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗが、水素原子を示し、
Ｘが、炭素数２〜３のカルボキシアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、メタ位又はパラ位に置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、炭素数２〜７のモノもしくはジアルキルアミジノ基、ピリジル基、カルボキシル基、アミジノ基、炭素数３〜６のジアルキルアミノカルボニル基、炭素数３〜６のジアルキルアミノスルホニル基、イミダゾリン−２−イル−アミノ基、ピロリジル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが（１２-2-1）、（１２−３）のいずれかを示す、
ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｚが２−アセトアミド−２−エトキシカルボニルエテニル基、２−アセトアミド−２−メトキシカルボニルエテニル基、２−アセトアミド−２−カルボキシルエテニル基、又は２−カルボキシ−２−オキソエチル基のいずれかである、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｘがエトキシカルボニルメチル基又はカルボキシメチル基のいずれかである、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、一般式（１）中、Ｖが、パラ位に置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、アミジノ基、カルボキシル基、ジメチルアミノカルボニル基、１−ピロリジルカルボニル基、４−ピペリジルオキシ基又は１−アセトイミドイル−４−ピペリジルオキシ基のいずれかである、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
又は、一般式（１）中、Ｌが式（２）有機基を示し、
Ｗが、水素原子を示し、
Ｘが、置換基を有するベンジル基を示し、置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、アミジノ基、ベンジルオキシカルボニル基、ヒドロキシ基、ハロゲノ基、アミジノピペリジルオキシ基もしくは炭素数１〜３のアルキル基があげられ、
Ｖが、水素原子、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニル、ピリジンカルボニル、ピペリジンカルボニル基もしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル、ベンゼンスルホニル基を示し、置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数２〜７のヒドロキシカルボニルアルキル基、炭素数３〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが水素原子、炭素数１〜６のアルキル基、ハロゲノ基または式（１２−１）、（１２−２）、（１２−３）のいずれかを示す、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
ここで、Ｘが、置換基を有するベンジル基を示し、置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基があげられ、
Ｖが、水素原子、ベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチルまたは炭素数１〜６のアルカンスルホニル基を示し、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが水素原子または式（１２−１）のいずれかを示す、ベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
より具体的には、これらに限定されるものではないが、実施例に記載の化合物が好ましい。
特に、（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−（４−ジメチルカルバモイルベンゾイルアミノ）ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−（４−カルボキシルベンゾイルアミノ）ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（１−（１−イミノエチル）ピペリジル−４−オキシ）ベンゾイルアミノ］ブタン酸又は（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］ブタン酸よりなる群の中から選ばれるベンズアミジン誘導体又はその医薬的に許容しうる塩が好ましい。
又、実施例７９、実施例２１３及び実施例２０６の化合物が好ましい。又、実施例１９３、実施例１９１の（３Ｒ）−４−〔５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ〕−３−〔４−（ピロリジン−１−カルボニル）ベンゾイルアミノ〕ブタン酸、実施例２１５、実施例２０５及び実施例７の化合物も好ましい。
一般式（１）の化合物におけるアミジノ基は適当な保護基により保護されていてもよい。
本発明においてアルキルは分岐、環を含んでもよい。例えばアルキル基にはシクロヘキシルメチル基等が含まれる。アリールとは芳香族炭化水素環基のみならず、Ｏ、Ｎ及びＳから選ばれる１〜３個の複素原子を有する複素芳香環基をも示している。アリール基を具体的に挙げるとフェニル、ピリジル、イミダゾーリル、ピローリル基等があり、例えばアリールアルケニル基には、２−（４−ピリジル）ビニル基等が含まれる。またジアルキルアミジノ基とは、Ｎ，Ｎ−ジアルキルアミジノ基およびＮ，Ｎ’−ジアルキルアミジノ基を示している。ジアルキルカルバモイル基、ジアルキルアミジノ基、ジアルキルアミノ基、ジアルキルアミノアルキル基、ジアルキルアミノスルホニル基、ジアルキルグアニジノ基において二つのアルキル基は結合して環を構成しても良い。またこのときＣＨ2の１つがＯ、ＮＨ、Ｓで置換されていてもよく、またＣＨ2−ＣＨ2はＣＨ＝ＣＨで置換されていてもよい。例えばジアルキルカルバモイル基にはピロリジン−１−カルボニル基等が、ジアルキルアミジノ基には２−イミダゾリン−２−イル基、（ピロリジン−１−イル）（イミノ）メチル基等が、ジアルキルグアニジノ基にはイミダゾリン−２−アミノ基等が含まれる。またアシルとはアルキルカルボニルのみならずアリールカルボニルをも含んでいる。例えば炭素数１〜８のアシル基にはベンゾイル基等が含まれる。またアルコキシはアルキルオキシのみならずアリールオキシ、アラルキルオキシをも示している。例えばアルコキシ基にはシクロヘキシルオキシ基、フェノキシ基等が含まれ、アルコキシカルボニル基にはベンジルオキシカルボニル基等が含まれる。
本発明においてアリールとは芳香族炭化水素環基のみならず、芳香族複素環基をも示している。例えばアリールアルケニル基を具体的に挙げると、２−（４−ピリジル）ビニル基等がある。またジ−アルキルアミジノ基とはＮ，Ｎ−ジアルキルアミジノ基およびＮ，Ｎ’−ジアルキルアミジノ基を示している。ジ−アルキルカルバモイル基、ジ−アルキルアミジノ基、ジ−アルキルアミノ基、ジ−アルキルアミノアルキル基において二つのアルキル基は結合して環を構成しても良い。たとえばジ−アルキルカルバモイル基を具体的に挙げると１−ピロリジンカルボニル基等が、ジ−アルキルアミジノ基を具体的に挙げると２−イミダゾリン−２−イル基等が挙げられる。またアルコキシとはアルキルオキシのみならずアリールオキシをも示している。たとえばアルコキシカルボニルピペリジルオキシ基を具体的に挙げると、１−フェノキシカルボニル−４−ピペリジルオキシ基等が挙げられる。
また、本発明化合物は不斉炭素を有する場合があり、本発明化合物には幾何異性体、互変異性体、光学異性体などの各種の立体異性体の混合物や単離されたものが含まれる。
以下に本発明化合物（１）の代表的な製造法を説明する。
（Ｌが前記式（２）を示す場合の製造法）
窒素上を例えばベンジルオキシカルボニル基或いはｔ−ブトキシカルボニル基で保護したアミノアルキルハライド（１３）に、溶媒として例えばジメチルホルムアミド等を用い、例えば炭酸カリウム等の塩基存在下３−シアノフェノールを作用させることによりベンゾニトリル誘導体（１４）を得ることができる。そして得られたベンゾニトリル誘導体（１４）の窒素上の保護基は、例えば４規定塩化水素のジオキサン溶液等酸性溶液中で脱保護することによりアミン（１５）を得ることができる。
Figure 0004103147
続いて、前記一般式（１）において、Ｖが置換基を有するベンゾイル基、または置換基を有していてもよいシンナモイル基、ピペリジンカルボニル基、フェニルアセチル基あるいは前記式（６）の有機基で表される場合には、溶媒として例えばジクロロメタン等を用い、アミン（１５）に、例えばジイソプロピルエチルアミン等の塩基存在下、アシル化剤を作用させることにより、アミド（１６）を得ることができる。
また、前記一般式（１）において、Ｖが置換基を有していてもよい炭素数１〜６のアルカンスルホニル基、ベンゼンスルホニル基、ナフタレンスルホニル基で表される場合には、溶媒として例えばジメチルホルムアミド等を用い、アミン（１５）に、例えばトリエチルアミン等の塩基存在下、スルホニル化剤を作用させることによりアミド（１６）を得ることができる。
Figure 0004103147
ここで、前記一般式（１）において、Ｗが水素以外の有機基で表される場合には、溶媒として例えばジメチルホルムアミド等を用い、アミド（１６）に、例えば水素化ナトリウム等の塩基を作用させた後、アルキル化剤を作用させることにより窒素上にＷの導入されたアミド（１７）を得ることができる。
Figure 0004103147
こうして得られたアミド（１７）に対し、例えば塩化水素等のハロゲン化水素を含有する、例えばエタノール等のアルコールを作用させ、続いてアンモニアを反応させることによりシアノ基をアミジノ基へと変換することができる。この様な工程により一般式（１）においてＹが前記式（７）で表され、Ｚが水素原子で表される、ベンズアミジン誘導体（１８）を製造することができる。
Figure 0004103147
Ｚが２−オキソ−２−カルボキシエチル基で表される場合には５−シアノ−２−ヨードフェノールを出発原料として用い、前記（１６）の製造方法と同様にして４−ヨードベンゾニトリル誘導体（１９）を得た後、このものと例えば２−アセチルアミノアクリル酸メチルとを例えばヘック反応等の反応によって縮合させることによりアクリル酸誘導体（２０）へ導くことができる。そして、前記と同様にシアノ基をアミジノ基へと変換し、４位置換基上のエステル部位とエナミノ部位の加水分解を同時に行うことにより一般式（１）においてＹが前記式（７）で表され、Ｚが２−オキソ−２−カルボキシエチル基で表される、ベンズアミジン誘導体（２１）を製造することができる。
Figure 0004103147
（Ｌが前記式（３）を示す場合の製造法）
３−ニトロフェニルアルキルハライド（２２）を用いて前記（１４）の製造方法と同様にしてベンゾニトリル誘導体（２３）を得た後、例えば酢酸を溶媒として、例えば亜鉛を作用させることによりアミン（２４）を得ることができる。このアミンを用いて前記（１６）の製造方法と同様にしてアシル化またはスルホニル化を行ったのち、前記と同様にシアノ基をアミジノ基に変換することにより、一般式（１）においてＹが前記式（７）で表され、Ｚが水素原子で示されるベンズアミジン誘導体を得ることができる。
Figure 0004103147
（Ｌが前記式（４）を示す場合の製造法）
Ｖが置換基を有するベンゾイル基の場合、例えば後記実施例６３に示すように、オキソアルキルハライド（２５）を調製し、前記（１４）の製造方法と同様にしてベンゾニトリル誘導体（２６）が得られる。この時、オキソアルキルハライド（２５）のケトンは例えばアセタール等に変換して保護してから反応させても良い。ベンゾニトリル誘導体（２６）のシアノ基を前記と同様にアミジノ基に変換することにより一般式（１）においてＹが前記式（７）で表され、Ｚが水素原子で示されるベンズアミジン誘導体を得ることができる。
Figure 0004103147
（Ｌが前記式（５）を示す場合の製造法）
例えば後記実施例６７に示すように、カルボン酸（２７）を調製し、これを例えば塩基存在下クロロ蟻酸エチルを作用させることにより活性化し、適当なアミンを作用させることによりアミド（２８）を得ることができる。前記と同様にシアノ基をアミジノ基に変換することにより一般式（１）においてＹが前記式（７）で表され、Ｚが水素原子で示されるベンズアミジン誘導体を得ることができる。
Figure 0004103147
本発明のベンズアミジン誘導体は、又、以下に述べる様な工程にても製造する事ができる。
すなわち、窒素上を例えばベンジルオキシカルボニル基又はｔ−ブトキシカルボニル基で保護したアミノアルキルアルコール（２９）と３−シアノ−５−ヨードフェノールに、溶媒として例えばＴＨＦ等を用い、例えばトリフェニルホスフィン等の存在下、例えばアゾジカルボン酸ジエチル等のアゾジカルボニル化合物を作用させることによりベンゾニトリル誘導体（３０）を得ることができる。そして得られたベンゾニトリル誘導体（３０）の窒素上の保護基を、例えば４規定塩化水素のジオキサン溶液等の酸性溶液中で脱保護することによりアミン（３１）を得ることができる。
Figure 0004103147
（式中、Ｘは炭素数２〜３のカルボキシアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示す。）
続いて、溶媒として例えばジクロロメタン等を用い、アミン（３１）に、例えばトリエチルアミン等の塩基存在下、縮合剤を作用させることにより、カルボン酸（３２）との縮合を行い、アミド（３３）を得ることができる。
Figure 0004103147
（式中、Ａは、置換基を示す。）
こうして得られた、アミド（３３）と、溶媒として例えばアセトニトリル等を用い、例えば２−アセトアミドアクリル酸メチル等アクリル酸誘導体とを例えばヘック反応等の反応によって縮合させることによりアクリル酸誘導体（３４）へ導くことができる。
Figure 0004103147
前記のアクリル酸誘導体（３４）に対し、例えば塩化水素等のハロゲン化水素を含有する、例えばエタノール等のアルコールを作用させ、続いて炭酸アンモニウム等のアンモニウム塩を反応させることによりシアノ基をアミジノ基へと変換することができる。この様な工程により、一般式（１）においてＺが上記式（１２−３）で表されるベンズアミジン誘導体（３５）を製造することができる。
Figure 0004103147
Ｚが２−カルボキシ−２−オキソエチル基で表される場合にはベンズアミジン誘導体（３５）を、例えば塩化水素等のハロゲン化水素の水溶液中で４位置換基上のエステル部位とエナミノ部位の加水分解を同時に行うことにより一般式（１）においてＺが２−カルボキシ−２−オキソエチル基で表される、ベンズアミジン誘導体（３６）を製造することができる。
Figure 0004103147
このようにして製造される一般式（１）で表される化合物およびその塩は、公知の分離精製手段、例えば抽出、濃縮、減圧濃縮、溶媒抽出、晶析、再結晶、転溶、各種クロマトグラフィーなどにより単離精製することができる。
一般式（１）で示されるベンズアミジン誘導体の塩は医薬的に許容しうるものであれば良く、例えば塩酸、臭化水素酸、硫酸、硝酸、リン酸等の鉱酸、ギ酸、酢酸、乳酸、サリチル酸、マンデル酸、クエン酸、シュウ酸、マレイン酸、フマル酸、酒石酸、タンニン酸、リンゴ酸、トシル酸、メタンスルホン酸、ベンゼンスルホン酸などの有機酸との酸付加塩を挙げることができる。
一般式（１）で示される化合物またはその塩は、そのままあるいは各種の医薬組成物として投与される。このような医薬組成物の剤形としては、例えば錠剤、散財、丸剤、顆粒剤、カプセル剤、坐剤、溶液剤、糖衣剤、またはデボー剤にしてよく、普通の製剤助剤を用いて常法に従って製造する事ができる。例えば錠剤は、本発明の有効成分であるベンズアミジン誘導体を既知の補助物質、例えば乳糖、炭酸カルシウムまたは燐酸カルシウム等の不活性希釈剤、アラビアゴム、コーンスターチまたはゼラチン等の結合剤、アルギン酸、コーンスターチまたは前ゼラチン化デンプン等の膨化剤、ショ糖、乳糖またはサッカリン等の甘味剤、ペパーミント、アカモノ油またはチェリー等の香味剤、ステアリン酸マグネシウム、タルクまたはカルボキシメチルセルロース等の滑湿剤と混合することによって得られる。
一般式（１）で示されるベンズアミジン誘導体を抗凝固剤として使用する場合の投与経路は、経口、非経口のいずれであってもよく、投与量は患者の年齢、体重、状態、および投与法によって異なるが、成人への一日当りの投与量としては、通常、経口投与の場合で０．０１〜１０００ｍｇ、好ましくは０．１〜５０ｍｇであり、非経口投与の場合で１μｇ〜１００ｍｇ、好ましくは０．０１〜１０ｍｇである。
以下、実施例により本発明を詳細に説明する。これらは本発明の好ましい実施態様であり、本発明がこれら実施例に限定されるものではない。
なお、本実施例における、（１）式においてＺが２−カルボキシ−２−オキソエチル基で表せられる化合物の、ＤＭＳＯ−ｄ６中のＮＭＲスペクトルは、ケト体とエノール体の混合物のものであった。
実施例１
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−アミジノベンズチオアミド 二トリフルオロ酢酸塩の合成
工程１
ｔ−ブチル（２−ブロモエチル）カルバマートの合成
２−ブロモエチルアミン 臭化水素酸塩９．２２ｇ（４５ｍｍｏｌ）をジクロロメタン１００ｍｌに溶解し、ジ−ｔ−ブチルジカルボネート７．６４ｇ（３５ｍｍｏｌ）、トリエチルアミン１０．０ｇ（９９ｍｍｏｌ）、４−（ジメチルアミノ）ピリジン１００ｍｇ（０．８２ｍｍｏｌ）を加え一晩撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ５．９９ｇ（２６．７ｍｍｏｌ） 収率 ７６％
H-NMR(CDCl3)δ1.45(1H,s),3.46(2H,dt),3.51(2H,t),4.95(1H,br)
工程２
３−［２−（ｔ−ブトキシカルボニルアミノ）エトキシ］ベンゾニトリルの合成
ｔ−ブチル（２−ブロモエチル）カルバマート５．８５ｇ（２９ｍｍｏｌ）をジメチルホルムアミド１００ｍｌに溶解し、３−ヒドロキシベンゾニトリル２．３８ｇ（２６．４ｍｍｏｌ）、炭酸カリウム３．０４ｇ（５３ｍｍｏｌ）、ヨウ化ナトリウム４．３１ｇ（５３ｍｍｏｌ）を加え５０℃で６時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ３．３３ｇ（１３．３ｍｍｏｌ） 収率 ５１％
H-NMR(CDCl3)δ1.44(1H,s),3.55(2H,dt),4.05(2H,t),4.95(1H,brs),7.12(1H,d),7.14(1H,s),7.26(1H,d),7.38(1H,t)
工程３
３−（２−アミノエトキシ）ベンゾニトリルの合成
３−［２−（ｔ−ブトキシカルボニルアミノ）エトキシ］ベンゾニトリル１．４１ｇを４規定塩化水素のジオキサン溶液２０ｍｌに溶解し室温で２時間撹拌した。溶媒を留去し、残渣をジクロロメタンに懸濁し、濾取することにより表題化合物の塩酸塩を得た。
収量 ０．８９ｇ（４．４８ｍｍｏｌ） 収率 ８３％
更に、この塩酸塩を１規定水酸化ナトリウム水溶液に溶解し、酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
H-NMR(CDCl3)δ3.10(2H,t),4.00(2H,t),7.15(1H,d),7.17(1H,s),7.25(1H,d),7.37(1H,t)
工程４
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミドの合成
４−シアノ安息香酸１．１３ｇ（７．６８ｍｍｏｌ）、Ｎ−メチルモルホリン１．６ｍｌ（１４．１ｍｍｏｌ）をジメチルホルムアミド３０ｍｌに溶解し、氷水冷下クロロギ酸エチル０．６７ｍｌ（７．０５ｍｍｏｌ）を加えた。５分間撹拌した後、３−（２−アミノエトキシ）ベンゾニトリル１．２７ｇ（６．４１ｍｍｏｌ）を加え、室温で一時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 １．２９ｇ（４．４３ｍｍｏｌ） 収率 ６９％
MS(FAB,m/z)292(MH+)
H-NMR(CDCl3)δ3.91(2H,dt),4.19(2H,t),6.78(1H,br),7.14(1H,d),7.17(1H,s),7.28(1H,d),7.39(1H,t),7.75(2H,d),7.90(2H,d)
工程５
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズチオアミドの合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミド１．４６ｇ（５．００ｍｍｏｌ）をトルエン５０ｍｌに溶解し、２，４−ビス（４−メトキシフェニル）−１，３−ジチア−２，４−ジホスフェタン−２，４−ジスルフィド３．０３ｇ（７．５ｍｍｏｌ）を加え、４時間加熱環流した。析出物をろ過して除いた後、減圧下溶媒を留去した。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．１６ｇ（３．７７ｍｍｏｌ） 収率 ７５％
H-NMR(CDCl3)δ3.85(2H,dt),4.30(2H,t),7.15(1H,d),7.17(1H,s),7.24(1H,d),7.39(1H,t),7.65(2H,d),7.81(2H,d),8.02(1H,br)
工程６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−アミジノベンズチオアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズチオアミド１．１６ｇ（３．７７ｍｍｏｌ）を４規定塩化水素のジオキサン溶液１８ｍｌに溶解したものに塩化水素を３０％含有する（ｗ／ｖ）エタノール２ｍｌを加えた。室温で９６時間撹拌した後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液２０ｍｌに溶解して室温で２４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ９０９ｍｇ（１．５９ｍｍｏｌ） 収率 ４２％
MS(ESI,m/z)342(MH+)
H-NMR(DMSO-d6)δ4.12(2H,dt),4.41(2H,t),7.35(1H,d),7.40(1H,d),7.41(1H,s),7.55(1H,t),7.82(2H,d),7.88(2H,d),9.20(2H,br),9.30(4H,br),9.39(2H,br),9.47(1H,t)
実施例２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−カルバモイルベンズアミド トリフルオロ酢酸塩の合成
工程１
ベンジル−Ｎ−（２−ブロモエチル）カルバマートの合成
２−ブロモエチルアミン 臭化水素酸塩１０ｇ（４９ｍｍｏｌ）、トリエチルアミン１５ｍｌをジクロロメタンに溶解し、ベンジルクロロホルマート７．８ｍｌ（４９ｍｍｏｌ）を氷冷下加え、室温で撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １０．６ｇ（４１ｍｍｏｌ） 収率 ８４％
H-NMR(CDCl3)δ3.45(2H,t),3.60(2H,dt),5.10(2H,s),5.20(1H,brs),7.30-7.38(5H,m)
工程２
３−（２−アミノエトキシ）ベンゾニトリル臭化水素酸塩の合成
ベンジル−Ｎ−（２−ブロモエチル）カルバマート８ｇ、３−ヒドロキシベンゾニトリル３．７ｇ、炭酸カルシウム４．３ｇ、ヨウ化カリウム５．１ｇ、ヨウ化テトラブチルアンモニウム１．１ｇをジメチルホルムアミド中６０℃で撹拌した。酢酸エチルを抽出溶媒として常法に従って処理した後、シリカゲルクロマトグラフィーで精製し３−［２−（ベンジルオキシカルボニルアミノ）エトキシ］ベンゾニトリルを得た。これに２０％臭化水素を含む酢酸を氷冷下加え室温で２時間撹拌した。溶媒を留去し残留物を酢酸エチルで洗浄し表題化合物を得た。
収量 ４ｇ
H-NMR(DMSO-d6)δ3.25(2H,m),4.25(2H,t),7.35(1H,d),7.45(1H,d),7.50(1H,s),7.55(1H,t),8.00(3H,br)
工程３
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸 メチルエステルの合成
３−（２−アミノエトキシ）ベンゾニトリル臭化水素酸塩１．５０ｇ（６．２mmol）、トリエチルアミン３ｍｌをジメチルホルムアミド１５ｍｌ中氷冷下撹拌し、そこへテレフタル酸モノメチルエステルクロライド１．２３ｇ（６．２mmol）をゆっくりと加え３時間撹拌した。室温に戻した後、反応液を１規定塩酸で希釈し、酢酸エチルで抽出、有機層を飽和炭酸水素ナトリウム水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 １．４ｇ（４．３ｍｍｏｌ） 収率 ７０％
H-NMR(CDCl3)δ3.90(2H,dt),3.93(3H,s),4.20(2H,t),6.60(1H,br),7.16(1H,d),7.17(1H,s),7.27(1H,d),7.39(1H,t),7.84(2H,d),8.12(2H,d)
工程４
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−カルバモイルベンズアミドの合成
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸 メチルエステル１００ｍｇ（０．３１ｍｍｏｌ）を２８％アンモニア水１００ｍｌ中で一晩撹拌した。反応液を減圧留去し、１規定塩酸を加え酢酸エチルで抽出、有機層を飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 ９８ｍｇ（０．３２ｍｍｏｌ） 収率 １００％
H-NMR(DMSO-d6)δ3.62(2H,dt),4.20(2H,t),7.32(1H,d),7.40(1H,d),7.44-7.52(3H,m),7.88-7.96(4H,m),8.06(1H,br),8.80(1H,t)
工程５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−カルバモイルベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−カルバモイルベンズアミド９５ｍｇを用いて実施例１工程６と同様にして表題化合物を得た。
収量 ４０．３ｍｇ（０．０９ｍｍｏｌ） 収率 ３０％
MS(ESI,m/z)327(MH+)
H-NMR(DMSO-d6)δ3.70(2H,dt),4.20(2H,t),7.32-7.40(3H,m),7.48(1H,br),7.54(1H,t),7.89-7.97(4H,m),8.60(1H,br),8.84(1H,brt),9.06(2H,brs),9.28(2H,brs)
実施例３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルカルバモイル）ベンズアミド トリフルオロ酢酸塩の合成
工程１
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸の合成
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸メチルエステル３１０ｍｇ（１ｍｍｏｌ）をエタノール１５ｍｌ、ＴＨＦ１５ｍｌ中撹拌し、１規定水酸化ナトリウム水溶液３ｍｌを加え、一晩室温で撹拌した。反応液を減圧留去後、１規定 塩酸を加え酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 ２９９ｍｇ（０．９６ｍｍｏｌ） 収率 ９６％
H-NMR(DMSO-d6)δ3.65(2H,dt),4.20(2H,t),7.32(1H,d),7.40(1H,d),7.44-7.52(2H,m),7.94(2H,d),8.02(2H,d),8.85(1H,brt)
工程２
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルカルバモイル）ベンズアミドの合成
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸１４０ｍｇ（０．４５ｍｍｏｌ）をジメチルホルムアミド中撹拌し、氷冷下トリエチルアミン５０ｍｇ（０．５ｍｍｏｌ）、クロロ蟻酸エチル４８ｍｇ（０．４５ｍｍｏｌ）を加え５分間撹拌し酸無水物とした後、５０％ジメチルアミン水溶液１ｍｌ（過剰量）を加えた。室温に戻して２時間撹拌した後、１規定塩酸で希釈し、酢酸エチルで抽出、有機層を飽和炭酸水素ナトリウム水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 １０２ｍｇ（０．３０ｍｍｏｌ） 収率 ６７％
H-NMR(CDCl3)δ2.90(3H,br),3.10(3H,br),3.90(2H,dt),4.20(2H,t),6.80(1H,br),7.16(1H,d),7.17(1H,s),7.26(1H,d),7.39(1H,t),7.45(2H,d),7.80(2H,d)
工程３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ，Ｎ−ジメチルカルバモイル）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ，Ｎ−ジメチルカルバモイル）ベンズアミド１００ｍｇ（０．３２ｍｍｏｌ）を４規定塩化水素を含むジオキサン５ｍｌ中で撹拌し、エタノール０．５ｍｌを加えて室温で２日間撹拌後溶媒を減圧留去した。得た残渣をエタノール１０ｍｌ中撹拌し、アンモニウムカルボナート８０ｍｇを加え５日間室温で撹拌し、溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ９５ｍｇ（０．２ｍｍｏｌ） 収率 ６３％
MS(ESI,m/z)355(MH+)
H-NMR(DMSO-d6)δ2.85(3H,br),3.00(3H,br),3.65(2H,dt),4.22(2H,t),7.31-7.41(3H,m),7.48(2H,d),7.54(1H,t),7.91(2H,d),8.80(1H,t),9.05(2H,br),9.30(2H,br)
実施例４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ−メチル−Ｎ−エチルカルバモイル）ベンズアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ−メチル−Ｎ−エチルカルバモイル）ベンズアミドの合成
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸２５８ｍｇ（０．８３ｍｍｏｌ）、Ｎ−エチル−Ｎ−メチルアミン５３ｍｇ（０．９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）１２９ｍｇ（０．８３ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１５９ｍｇ（０．８３ｍｍｏｌ）をジクロロメタン１０ｍｌ中室温で一晩撹拌した。１規定塩酸で希釈しジクロロメタンで抽出、有機層を１規定水酸化ナトリウム水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 ２８８ｍｇ（０．８２ｍｍｏｌ） 収率 ９９％
H-NMR(CDCl3)δ1.00-1.30(3H,m),2.82-3.62(5H,m),3.83(2H,dt),4.20(2H,t),7.12-7.41(7H,m),7.78(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ−メチル−Ｎ−エチルカルバモイル）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ−メチル−Ｎ−エチルカルバモイル）ベンズアミド２８０ｍｇ（０．８ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ２４２ｍｇ（０．５ｍｍｏｌ） 収率 ６３％
MS(ESI,m/z)369(MH+)
H-NMR(DMSO-d6)δ1.00-1.20(3H,brm),2.80-3.00(3H,br),3.10-3.50(2H,m),3.70(2H,dt),4.20(2H,t),7.34(1H,d),7.39(1H,d),7.40(1H,s),7.43-7.50(2H,br),7.54(1H,t),7.91(2H,d),8.80(1H,br),9.10(2H,br),9.30(2H,br)
実施例５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（２−イミダゾリン−２−イル）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−エトキシカルボンイミドイル安息香酸 エチルエステル 塩酸塩の合成
４−シアノ安息香酸 エチルエステル５．１６ｇ（２９ｍｍｏｌ）を４規定塩化水素を含むジオキサン５０ｍｌ中で撹拌しそこへエタノール５ｍｌを加え室温で４日間撹拌した。溶媒を留去し、残留物を酢酸エチルで洗浄、乾燥し表題化合物を得た。
収量３．２４ｇ（１２．６ｍｍｏｌ） 収率 ４３％
H-NMR(DMSO-d6)δ1.35(3H,t),1.50(3H,t),4.40(2H,q),4.65(2H,q),8.18(2H,d),8.25(2H,d)
工程２
４−（２−イミダゾリン−２−イル）安息香酸 エチルエステルの合成
４−エトキシカルボンイミドイル安息香酸 エチルエステル 塩酸塩２．９６ｇ（１１．５ｍｍｏｌ）、エチレンジアミン６９０ｍｇ（１１．５ｍｍｏｌ）をエタノール１００ｍｌ中６０℃で４時間撹拌した。溶媒を留去し、１規定水酸化ナトリウム水を加えてジクロロメタンで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 ２．１５ｇ（９．８５ｍｍｏｌ） 収率 ８６％
H-NMR(CDCl3)δ1.40(3H,t),3.80(4H,br),4.40(2H,q),7.80(2H,d),8.02(2H,d)
工程３
４−（２−イミダゾリン−２−イル）安息香酸 塩酸塩の合成
４−（２−イミダゾリン−２−イル）安息香酸 エチルエステル１ｇ（４．５８ｍｍｏｌ）を塩酸４ｍｌ、酢酸８ｍｌ中、加熱環流し、溶媒を留去して表題化合物を得た。
収量 １．０４ｇ（４．５９ｍｍｏｌ） 収率 １００％
H-NMR(DMSO-d6)δ4.00(4H,s),8.20(4H,s),11.00(2H,br)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（２−イミダゾリン−２−イル）ベンズアミド 二トリフルオロ酢酸塩の合成
４−（２−イミダゾリン−２−イル）安息香酸 塩酸塩４００ｍｇ（１．７６ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル臭化水素酸塩４２８ｍｇ（１．７６ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）３０１ｍｇ（１．９４ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３７２ｍｇ（１．９４ｍｍｏｌ）、トリエチルアミン２００ｍｇ（２．００ｍｍｏｌ）をジメチルホルムアミド中室温で一晩撹拌した。溶媒を減圧留去し、オクタドデシル基化学結合型シリカゲルを充填剤とする逆相中圧液体クロマトグラフィーに付し、メタノールと水の混合溶媒で溶出した。目的物のフラクションを溶媒留去し、残留物を酢酸エチルで洗浄することにより、４００ｍｇの縮合体を得た。このうち１００ｍｇを実施例３工程３と同様にして表題化合物を得た。
収量 １１７ｍｇ（０．２ｍｍｏｌ）
MS(ESI,m/z)352(MH+)
H-NMR(DMSO-d6)δ3.70(2H,dt),4.00(4H,s),4.22(2H,t),7.30-7.42(3H,m),7.55(1H,t),8.02(2H,d),8.10(2H,d),9.05(1H,t),9.20-9.35(4H,br),10.7(2H,s)
実施例６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１−ピペリジンカルボニル）ベンズアミド トリフルオロ酢酸塩の合成
工程１
４−（１−ピペリジンカルボニル）安息香酸の合成
ピペリジン６ｍｌをジクロロメタン中、０℃で撹拌し、テレフタル酸モノメチルエステルクロライド３ｇ（１５ｍｍｏｌ）をジクロロメタンに溶かして加えた。室温にもどし２時間撹拌した後、１規定塩酸で希釈しジクロロメタンで抽出、有機層を飽和炭酸水素ナトリウム水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去して得た残留物をエタノール中撹拌し、１規定水酸化ナトリウム水溶液３０ｍｌを加え室温で一晩撹拌した。溶媒を留去して反応液を濃縮し、１規定塩酸で希釈し酢酸エチルで抽出、有機層を飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 ２．８１ｇ（１２ｍｍｏｌ） 収率 ８０％
H-NMR(CDCl3)δ1.45-1.75(6H,br),3.33(2H,br),3.75(2H,br),7.50(2H,d),8.15(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１−ピペリジンカルボニル）ベンズアミド トリフルオロ酢酸塩の合成
４−（１−ピペリジンカルボニル）安息香酸３００ｍｇ（１．２９ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２５５ｍｇ（１．２９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）２００ｍｇ（１．２９ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２４７ｍｇ（１．２９ｍｍｏｌ）、トリエチルアミン１３０．５ｍｇ（１．２９ｍｍｏｌ）を用いて実施例４工程１と同様にして得たＮ−［２−（３−シアノフェノキシ）エチル］−４−（１−ピペリジンカルボニル）ベンズアミド全量を実施例３工程３と同様にして表題化合物を得た。
収量 ３７０ｍｇ（０．７３ｍｍｏｌ） 収率 ５６％
MS(ESI,m/z)395(MH+)
H-NMR(DMSO-d6)δ1.40-1.65(6H,br),3.25(2H,br),3.60(2H,br),3.65(2H,dt),4.25(2H,t),7.34(1H,d),7.39(1H,d),7.40(1H,s),7.45(2H,d),7.54(1H,t),7.91(2H,d)
実施例７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルアミジノ）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（Ｎ、Ｎ−ジメチルアミジノ）安息香酸 エチルエステルの合成
４−エトキシカルボンイミドイル安息香酸 エチルエステル 塩酸塩１ｇ（３．９ｍｍｏｌ）をエタノール３ｍｌ、５０％ジメチルアミン水溶液１０ｍｌ中で一晩撹拌した後溶媒を留去し、４規定塩化水素を含むジオキサン１０ｍｌ、エタノール１ｍｌを加え室温で５日間撹拌した後溶媒を留去、１規定水酸化ナトリウムを加えジクロロメタンで抽出、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して表題化合物を得た。
収量 ６７１ｍｇ（３．０５ｍｍｏｌ） 収率 ７８％
H-NMR(CDCl3)δ1.40(3H,t),2.95(6H,s),4.30(1H,br),4.40(2H,q),7.40(2H,d),8.10(2H,d)
工程２
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルアミジノ）ベンズアミド トリフルオロ酢酸塩
４−（Ｎ、Ｎ−ジメチルアミジノ）安息香酸 エチルエステル６７０ｍｇ（３．０ｍｍｏｌ）を６規定塩酸２０ｍｌ中加熱環流した。溶媒を留去し得た残留物にジクロロメタン１０ｍｌ、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩６００ｍｇ（３．０ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩５７５ｍｇ（３．０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール４０５ｍｇ（３．０ｍｍｏｌ）、トリエチルアミン３０３ｍｇ（３．０ｍｍｏｌ）を加え室温で５日間撹拌した。１規定 水酸化ナトリウム水溶液を加えジクロロメタンで抽出、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去して得た残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ７１６ｍｇ（１．５９ｍｍｏｌ） 収率 ５３％
H-NMR(DMSO-d6)δ2.98(3H,s),3.22(3H,s),3.65(2H,dt),4.22(2H,t),7.30-7.53(4H,m),7.70(2H,d),8.05(2H,d),8.92(1H,br),9.00(1H,s),9.40(1H,s)
工程３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルアミジノ）ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルアミジノ）ベンズアミド トリフルオロ酢酸塩５０６ｍｇ（１．１ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ３８９ｍｇ（０．６７ｍｍｏｌ） 収率 ６１％
MS(ESI,m/z)354(MH+)
H-NMR(DMSO-d6)δ2.95(3H,s),3.22(3H,s),3.70(2H,dt),4.22(2H,t),7.34(1H,d),7.38-7.44(2H,m),7.54(1H,t),7.70 2H,d),8.07(2H,d),9.00-9.42(7H,m)
実施例８
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１，４，５，６−テトラヒドロ−ピリミジン−２−イル）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１，４，５，６−テトラヒドロ−ピリミジン−２−イル）ベンズアミド トリフルオロ酢酸塩の合成
４−シアノ安息香酸１０ｇ（６８ｍｍｏｌ）を４規定塩化水素を含むジオキサン１００ｍｌ、エタノール１０ｍｌ中で２日間撹拌し、溶媒を留去して得た残留物を酢酸エチルで洗浄して得た４−エトキシカルボンイミドイル安息香酸およびそのエステルの混合物１０．９ｇのうち５００ｍｇ、およびプロピレンジアミン１６２ｍｇ（２．１８ｍｍｏｌ）をエタノール１５ｍｌ中６０℃で二時間撹拌した。溶媒を留去し、濃塩酸を加えて６０℃で５時間撹拌後、溶媒を留去して得た残留物を酢酸エチルで洗浄して、４−（１，４，５，６−テトラヒドロ−ピリミジン−２−イル）安息香酸粗製物２９０ｍｇ（１．２ｍｍｏｌ）を得た。そこへ３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２３８ｍｇ（１．２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２３０ｍｇ（１．２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）１８６ｍｇ（１．２ｍｍｏｌ）、トリエチルアミン１２２ｍｇ（１．２ｍｍｏｌ）、ジメチルホルムアミド１０ｍｌを加え、室温で４日間撹拌した。溶媒を減圧留去して、１規定水酸化ナトリウム水溶液を加えてジクロロメタンで抽出、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １２５ｍｇ
H-NMR(DMSO-d6)δ2.00(2H,m),3.50(4H,br),3.65(2H,dt),4.20(2H,t),7.32(1H,d),7.41(1H,d),7.44-7.52(2H,m),7.81(2H,d),8.04(2H,d),8.94(1H,t),10.00(2H,s)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１，４，５，６−テトラヒドロ−ピリミジン−２−イル）ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１，４，５，６−テトラヒドロ−ピリミジン−２−イル）ベンズアミド１１７ｍｇ（０．２５ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ３７ｍｇ（０．０６ｍｍｏｌ） 収率 ２４％
MS(ESI,m/z)366(MH+)
H-NMR(DMSO-d6)δ2.00(2H,br),3.50(4H,br),3.70(2H,dt),4.25(2H,t),7.30-7.45(3H,m),7.55(1H,t),7.82(2H,d),8.06(2H,d),9.03(1H,br),9.30(2H,br),9.40(2H,br),10.1(2H,br)
実施例９
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１−ピロリジンカルボニル）ベンズアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１−ピロリジンカルボニル）ベンズアミドの合成
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸２４５ｍｇ（０．７９ｍｍｏｌ）、ピロリジン６２ｍｇ（０．８７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）１２３ｍｇ（０．７９ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１５１ｍｇ（０．７９ｍｍｏｌ）を用いて実施例４工程１と同様にして表題化合物を得た。
収量 ２７７ｍｇ（０．７６ｍｍｏｌ） 収率 ９６％
H-NMR(CDCl3)δ1.80-2.00(4H,m),3.30-3.70(4H,m),3.85(2H,dt),4.20(2H,t),7.14-7.28(4H,m),7.38(1H,t),7.48(2H,d),7.79(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１−ピロリジンカルボニル）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１−ピロリジンカルボニル）ベンズアミド２７０ｍｇ（０．７４ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ２３８ｍｇ（０．４８ｍｍｏｌ） 収率 ６５％
MS(ESI,m/z)381(MH+)
H-NMR(DMSO-d6)δ1.75-1.90(4H,m),3.30-3.50(4H,m),3.70(2H,dt),4.20(2H,t),7.34(1H,d),7.39(1H,d),7.40(1H,s),7.54(1H,t),7.59(2H,d),7.91(2H,d),8.80(1H,t),9.10(2H,br),9.30(2H,br)
実施例１０
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（Ｅ）−２−（ピリジン−４−イル）ビニル］ベンズアミド 二トリフルオロ酢酸塩の合成
４−（ジエトキシホスホリルメチル）安息香酸メチル４１２ｍｇ（１．４４ｍｍｏｌ）をテトラヒドロフラン５０ｍｌに溶解させ、氷冷下、水素化ナトリウム６３ｍｇ（１．４４ｍｍｏｌ）を加え、３０分撹拌後室温に戻して３０分撹拌した。ピリジン−４−アルデヒド１５４ｍｇ（１．４４ｍｍｏｌ）を加え２０時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物に濃塩酸５ｍｌを加え、６０℃で２２時間撹拌した。溶媒を留去して得られた残留物をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．５８ｍｌ（４．１７ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１７６ｍｇ（０．９２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１２４ｍｇ（０．９２ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩１８２ｍｇ（０．８３ｍｍｏｌ）を加え、１８時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様にして表題化合物を得た。
収量 １５０ｍｇ（０．２４ｍｍｏｌ） 収率 ４７％
MS(ESI,m/z)387(MH+)
H-NMR(DMSO-d6)δ3.70(2H,dt),4.26(2H,t),7.32-7.50(3H,m),7.54(1H,dd),7.66-7.84(5H,m),7.95(2H,d),8.64(2H,d),8.82-8.90(1H,m),9.18(2H,br),9.39(2H,br)
実施例１１
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１Ｈ−ピロール−１−イル）ベンズアミド トリフルオロ酢酸塩の合成
４−（１Ｈ−ピロール−１−イル）安息香酸２１０ｍｇ（１．１２ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．４７ｍｌ（３．３６ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２３６ｍｇ（１．２４ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１６７ｍｇ（１．２４ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２２２ｍｇ（１．１２ｍｍｏｌ）を加え、１８時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ２４３ｍｇ（０．５３ｍｍｏｌ） 収率 ４７％
MS(ESI,m/z)349(MH+)
H-NMR(DMSO-d6)δ3.69(4H,q),3.63(2H,dt),4.24(2H,t),6.31(2H,dd),7.30-7.44(3H,m),7.45-7.60(3H,m),7.69(2H,d),7.95(2H,d),8.77(1H,br),9.12(2H,br),9.28(2H,br)
実施例１２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−シクロヘキシルオキシベンズアミド トリフルオロ酢酸塩の合成
工程１
４−シクロヘキシルオキシ安息香酸エチルの合成
４−ヒドロキシ安息香酸エチル８２２ｍｇ（４．９５ｍｍｏｌ）をテトラヒドロフラン２０ｍｌに溶解させ、シクロヘキサノール５４５ｍｇ（５．４５ｍｍｏｌ）、トリフェニルホスフィン１．５６ｇ（５．９４ｍｍｏｌ）、ジエチルアゾジカルボキシレート２０２ｍｇ（１．５０ｍｍｏｌ）を加え、２２時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ６４０ｍｇ（２．５８ｍｍｏｌ） 収率 ５２％
H-NMR(CDCl3)δ1.32-1.44(3H,m),1.37(3H,t),1.48-1.63(3H,m),1.74-1.87(2H,m),1.93-2.20(2H,m),4.28-4.40(1H,m),4.34(2H,q),6.90(2H,d),7.97(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−シクロヘキシルオキシベンズアミド トリフルオロ酢酸塩の合成
４−シクロヘキシルオキシ安息香酸エチル２３７ｍｇ（０．９５ｍｍｏｌ）に１規定水酸化ナトリウム３ｍｌ、エタノール１０ｍｌを加え２０時間撹拌した。反応液を１規定塩酸で酸性にし、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物ををジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．７３ｍｌ（５．２５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２００ｍｇ（１．０５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１４１ｍｇ（１．０５ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩１８８ｍｇ（０．９５ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １６２ｍｇ（０．７７ｍｍｏｌ） 収率 ３４％
MS(ESI,m/z)382(MH+)
H-NMR(DMSO-d6)δ1.30-1.58(6H,m),1.64-1.75(2H,m),1.88-1.98(2H,m),3.67(2H,dt),4.20(2H,t),4.37-4.48(2H,m),6.98(2H,d),7.33(1H,d),7.39(2H,br),7.53(1H,dd),7.81(2H,d),8.56(1H,br),9.08(2H,br),9.26(2H,br)
実施例１３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−ジエチルアミノベンズアミド トリフルオロ酢酸塩の合成
４−ジエチルアミノ安息香酸２１０ｍｇ（１．０９ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．７６ｍｌ（５．４５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２２９ｍｇ（１．２０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１６２ｍｇ（１．２０ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２１５ｍｇ（１．０９ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ４１０ｍｇ（０．８８ｍｍｏｌ） 収率 ８０％
MS(ESI,m/z)355(MH+)
H-NMR(DMSO-d6)δ1.10(6H,t),3.38(4H,q),3.63(2H,dt),4.18(2H,t),6.66(2H,d),7.32-7.40(3H,m),7.53(1H,dd),7.71(2H,d),8.31(1H,br),9.04(2H,br),9.28(2H,br)
実施例１４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［２−（ピリジン−４−イル）エチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（Ｅ）−２−（ピリジン−４−イル）ビニル］ベンズアミド 二トリフルオロ酢酸塩５０ｍｇ（０．０８ｍｍｏｌ）をメタノール５ｍｌに溶解させ、パラジウム−炭素５０ｍｇを加え、水素存在下２０時間撹拌した。セライト濾過後、溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ７ｍｇ（０．０１ｍｍｏｌ） 収率 １４％
MS(ESI,m/z)389(MH+)
H-NMR(DMSO-d6)δ3.06(2H,dt),3.18(2H,dt),3.66(2H,dt),4.22(2H,t),7.29-7.45(5H,m),7.54(1H,dd),7.80(4H,dd),8.66-8.80(3H,m),9.30(2H,br)
実施例１５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−ニトロベンズアミド トリフルオロ酢酸塩の合成
４−ニトロ安息香酸１９０ｍｇ（１．１４ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．４７ｍｌ（３．４２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２３９ｍｇ（１．２５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１６９ｍｇ（１．２５ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２２５ｍｇ（１．１４ｍｍｏｌ）を加え、２０時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。収量 ２９０ｍｇ（０．６６ｍｍｏｌ） 収率 ５８％
MS(ESI,m/z)329(MH+)
H-NMR(DMSO-d6)δ3.71(2H,dt),4.25(2H,t),7.34(1H,dd),7.40(2H,br),7.54(1H,t),8.09(2H,d),8.33(2H,d),9.10(1H,br),9.14(2H,br),9.28(2H,br)
実施例１６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−トリフルオロメチルベンズアミド トリフルオロ酢酸塩の合成
４−トリフルオロメチル安息香酸１９４ｍｇ（１．０２ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．４３ｍｌ（３．０６ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２１５ｍｇ（１．１２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１５２ｍｇ（１．１２ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２０２ｍｇ（１．０２ｍｍｏｌ）を加え、２０時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ２４０ｍｇ（０．５６ｍｍｏｌ） 収率 ５１％
MS(ESI,m/z)352(MH+)
H-NMR(DMSO-d6)δ3.69(2H,dt),4.24(2H,t),7.34(1H,dd),7.40(2H,br),7.54(1H,dd),7.86(2H,d),8.06(2H,d),8.99(1H,br),9.12(2H,br),9.28(2H,br)
実施例１７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−イソプロピルベンズアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−イソプロピルベンズアミドの合成
４−イソプロピル安息香酸２８３ｍｇ（１．７３ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン１．２ｍｌ（８．６５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３６３ｍｇ（１．９０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２５６ｍｇ（１．９０ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩３４２ｍｇ（１．２４ｍｍｏｌ）を加え、１８時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ４４０ｍｇ（１．４３ｍｍｏｌ） 収率 ８３％
H-NMR(CDCl3)δ2.96(6H,s),3.62(2H,dt),4.17(2H,t),6.70(2H,d),7.32-7.43(3H,m),7.54(1H,t),7.74(2H,d),8.36(1H,t),9.05(2H,br),9.28(2H,br)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−イソプロピルベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−イソプロピルベンズアミド４４０ｍｇ（１．４３ｍｍｏｌ）を出発原料として、実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １７０ｍｇ（０．３９ｍｍｏｌ） 収率 ２７％
MS(ESI,m/z)326(MH+)
H-NMR(DMSO-d6)δ1.20(3H,s),1.22(3H,s),2.83+3.03(1H,m),3.66(2H,dt),4.21(2H,t),7.33(2H,d),7.36-7.42(2H,m),7.53(1H,dd),7.79(2H,d),8.65(1H,br),9.16(2H,br),9.28(2H,br)
実施例１８
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピロリジン−１−イル）ベンズアミド トリフルオロ酢酸塩の合成
工程１
４−（ピロリジン−１−イル）安息香酸エチルの合成
４−アミノ安息香酸エチル１．６９ｇ（１０．２ｍｍｏｌ）をベンゼン１０ｍｌに溶解させ、１，４−ジブロモブタン２．１８ｇ（１０．１ｍｍｏｌ）、ジイソプロピルエチルアミン３．５３ｍｌ（２０．２ｍｍｏｌ）を加え、４８時間加熱還流した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して表題化合物粗製物を得た。
収量 １．０ｇ（４．５６ｍｍｏｌ） 収率 ４６％
H-NMR(CDCl3)δ1.37(3H,t),1.92-2.18(4H,m),3.21-3.47(3H,m),4.31(2H,q),6.50(2H,d),7.91(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピロリジン−１−イル）ベンズアミド トリフルオロ酢酸塩の合成
４−（ピロリジン−１−イル）安息香酸エチル３４３ｍｇ（１．５６ｍｍｏｌ）に濃塩酸５ｍｌを加え６０℃で２０時間撹拌した。溶媒を留去して得られた残留物をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン１．０９ｍｌ（７．８０ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３２９ｍｇ（１．７２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２３３ｍｇ（１．７２ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩３０８ｍｇ（１．５６ｍｍｏｌ）を加え１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ２２０ｍｇ（０．４３ｍｍｏｌ） 収率 ３０％
MS(ESI,m/z)352(MH+)
H-NMR(DMSO-d6)δ1.96(4H,t),3.27(4H,t),3.62(2H,dt),4.20(2H,t),6.52(2H,d),7.38-7.39(3H,m),7.53(1H,dd),7.74(2H,d),8.38(1H,br),9.29(2H,br),9.37(2H,br)
実施例１９
１−ベンゾイル−Ｎ−［２−（３−アミジノフェノキシ）エチル］ピペリジン−４−カルボキシアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミドの合成 （ｔ−ブトキシカルボニル）ピペリジン−４−カルボン酸２．５４ｇ（１１．１ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル２．００ｇ（１０．１ｍｍｏｌ）、トリエチルアミン１．４ｍｌ（１０．１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１．５０ｇ（１１．１ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２．１３ｇ（１１．１ｍｍｏｌ）をジメチルホルムアミド１５ｍｌ中、室温下一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し１−（ｔ−ブトキシカルボニル）−Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミド粗製物を得た。この粗製物を４規定塩化水素を含むジオキサン５ｍｌ（２０．１ｍｍｏｌ）とジオキサン１０ｍｌの混合液中、室温で４時間撹拌した。溶媒を留去し、１規定水酸化ナトリウム水溶液を加えて酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量１．７３ｇ（６．３４ｍｍｏｌ） 収率 ６３％
MS(ESI,m/z)274(MH+)
H-NMR(CDCl3)δ1.64(2H,ddd),1.84(2H,d),2.14(2H,s),2.28(1H,tt),2.64(2H,ddd),3.16(2H,dt),3.70(2H,t),4.06(2H,t),6.00(1H,brs),7.14(1H,d),7.15(1H,s),7.26(1H,d),7.38(1H,t)
工程２
１−ベンゾイル−Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミドの合成
安息香酸１７５ｍｇ（１．４３ｍｍｏｌ）、Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミド４３０ｍｇ（１．５８ｍｍｏｌ）、トリエチルアミン０．２２ｍｌ（１．５８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２１３ｍｇ（１．５８ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３０３ｍｇ（１．５８ｍｍｏｌ）をジメチルホルムアミド１０ｍｌ中、室温下一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量４５８ｍｇ（１．２１ｍｍｏｌ） 収率 ８５％
MS(ESI,m/z)378(MH+)
H-NMR(CDCl3)δ1.60-2.00(5H,m),2.38-2.40(2H,m),2.80-3.01(2H,m),3.62(2H,t),4.02(2H,t),6.40(1H,brs),7.15(2H,brs),7.25(1H,d),7.32-7.40(6H,m)
工程３
１−ベンゾイル−Ｎ−［２−（３−アミジノフェノキシ）エチル］ピペリジン−４−カルボキシアミド トリフルオロ酢酸塩の合成
１−ベンゾイル−Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミド４５８ｍｇ（１．２１ｍｍｏｌ）を４規定塩化水素を含むジオキサン１０ｍｌ中撹拌し、そこへ塩化水素を３０％含む（ｗ／ｖ）エタノール３．５ｍｌを加えて室温で３日間撹拌後、溶媒を減圧留去した。得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１５ｍｌに溶解して室温で２日間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量５１４ｍｇ（１．０１ｍｍｏｌ） 収率 ８４％
MS(ESI,m/z)395(MH+)
H-NMR(DMSO-d6)δ1.52(2H,t),1.60-1.80(2H,m),2.38-2.42(1H,m),2.80-3.10(2H,m),3.45(2H,t),3.50-3.64(1H,m),4.08(2H,t),4.20-4.50(1H,m),7.28(1H,d),7.30-7.48(5H,m),7.30-7.48(5H,m),7.51(1H,t),8.12(1H,t),9.22(4H,d)
実施例２０
１−ベンゼンスルホニル−Ｎ−［２−（３−アミジノフェノキシ）エチル］ピペリジン−４−カルボキシアミド トリフルオロ酢酸塩の合成
工程１
１−ベンゼンスルホニル−Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミドの合成
Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミド４３０ｍｇ（１．５８ｍｍｏｌ）をジメチルホルムアミド１０ｍｌに溶解し、トリエチルアミン０．２ｍｌ（１．４３ｍｍｏｌ）、ベンゼンスルホニルクロリド２５３ｍｇ（１．４３ｍｍｏｌ）を０℃で加え、１３時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し、表題化合物を得た。収量５６８ｍｇ（１．３７ｍｍｏｌ） 収率 ９６％
MS(ESI,m/z)414(MH+)
H-NMR(CDCl3)δ1.80(2H,dd),1.90(2H,td),2.05(1H,d),2.40(2H,td),3.62(2H,t),3.76(2H,dt),4.05(2H,t),6.00(1H,brs),7.10(2H,t),7.23(2H,d),7.40(2H,t),7.58(3H,td),7.78(2H,d)
工程２
１−ベンゼンスルホニル−Ｎ−［２−（３−アミジノフェノキシ）エチル］ピペリジン−４−カルボキシアミド トリフルオロ酢酸塩の合成
１−ベンゼンスルホニル−Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミド５６８ｍｇ（１．３７ｍｍｏｌ）を４規定塩化水素を含むジオキサン１０ｍｌ中撹拌し、そこへ塩化水素を３０％含む（ｗ／ｖ）エタノール３．５ｍｌを加えて室温で３日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１５ｍｌに溶解して室温で２日間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量５３３ｍｇ（０．９８ｍｍｏｌ） 収率 ７２％
MS(ESI,m/z)430(M+)
H-NMR(DMSO-d6)δ1.52(2H,t),1.72(2H,d),2.05-2.18(1H,m),2.30(2H,t),3.42(2H,t),3.60(2H,d),4.05(2H,t),7.26(1H,d),7.34(1H,s),7.38(1H,d),7.50(1H,t),7.62(1H,d),7.63-7.77(5H,m),8.00(1H,t),9.22(4H,d)
実施例２１
１−ベンジル−Ｎ−［２−（３−アミジノフェノキシ）エチル］−ピペリジン−４−カルボキシアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−ピペリジン−４−カルボキシアミド４３０ｍｇ（１．５８ｍｍｏｌ）をジメチルホルムアミド１０ｍｌに溶解し、炭酸カリウム５４０ｍｇ（３．９３ｍｍｏｌ）、ベンジルブロマイド０．１６ｍｌ（１．３１ｍｍｏｌ）を加え、５０℃で１３時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し、１−ベンジル−Ｎ−［２−（３−シアノフェノキシ）エチル］ピペリジン−４−カルボキシアミド粗製物を得た。この粗製物を４規定塩化水素を含むジオキサン１０ｍｌ中撹拌し、そこへ塩化水素を３０％含む（ｗ／ｖ）エタノール３．５ｍｌを加えて室温で３日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液２０ｍｌに溶解して室温で２日間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量５３２ｍｇ（０．８７５ｍｍｏｌ） 収率 ６７％
MS(ESI,m/z)381(MH+)
H-NMR(DMSO-d6)δ1.70(2H,t),1.90(2H,t),2.40(1H,t),2.90(2H,t),3.20-3.40(2H,m),3.42(2H,t),4.08(2H,t),4.15(2H,brs),7.28(1H,d),7.33(1H,s),7.34(1H,d),7.40-7.60(5H,m),8.26(1H,brs),9.30(4H,d),9.63-9.80(1H,m)
実施例２２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペリジン−１−イル）ベンズアミド トリフルオロ酢酸塩の合成
工程１
４−（ピペリジン−１−イル）安息香酸エチルの合成
４−アミノ安息香酸エチル２．１６ｇ（１３．１ｍｍｏｌ）をベンゼン２０ｍｌに溶解させ、１，５−ジブロモペンタン２．９７ｇ（１３．０ｍｍｏｌ）、ジイソプロピルエチルアミン４．５３ｍｌ（２６．０ｍｍｏｌ）を加え、４８時間加熱還流した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して表題化合物の粗生物を得た。
収量 １．５ｇ（６．４４ｍｍｏｌ） 収率 ４９％
H-NMR(CDCl3)δ1.37(3H,t),1.52-1.77(6H,m),3.26-3.37(4H,m),4.32(2H,q),6.85(2H,d),7.91(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペリジン−１−イル）ベンズアミド トリフルオロ酢酸塩の合成
４−（ピペリジン−１−イル）安息香酸エチル３１１ｍｇ（１．３３ｍｍｏｌ）に濃塩酸５ｍｌを加え６０℃で２０時間撹拌した。溶媒を留去して得られた残留物をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．９３ｍｌ（６．６５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２７９ｍｇ（１．４６ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１９９ｍｇ（１．４６ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２６４ｍｇ（１．３３ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ３１０ｍｇ（０．６５ｍｍｏｌ） 収率 ４８％
MS(ESI,m/z)367(MH+)
H-NMR(DMSO-d6)δ1.58(6H,br),3.28(4H,br),3.62(2H,dt),4.18(2H,t),6.94(2H,d),7.30-7.41(3H,m),7.53(1H,dd),7.73(2H,d),8.42(1H,br),9.03(2H,br),9.28(2H,br)
実施例２３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−１Ｈ−インドール−５−カルボキシアミド トリフルオロ酢酸塩の合成
１Ｈ−インドール−５−カルボキシリックアシッド２３７ｍｇ（１．４７ｍｍｏｌ）をジクロロメタン５ｍｌに溶解させ、トリエチルアミン１．０２ｍｌ（７．３５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３０９ｍｇ（１．６２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２１９ｍｇ（１．６２ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２９１ｍｇ（１．４７ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １６０ｍｇ（０．２９ｍｍｏｌ） 収率 ２０％
MS(ESI,m/z)323(MH+)
H-NMR(DMSO-d6)δ3.68(2H,dt),4.23(2H,t),6.52(1H,br),7.26-7.63(8H,m),8.14(1H,br),8.50-8.59(1H,m),9.12(1H,br),9.20(1H,br),9.20(2H,br)
実施例２４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−１−（４−ピリジル）ピペリジン−４−カルボキシアミド 二トリフルオロ酢酸塩の合成
工程１
１−（４−ピリジル）−ピペリジン−４−カルボン酸エチルの合成
４−クロロピリジン塩酸塩４．０ｇ（２６．６ｍｍｏｌ）、ピペリジン−４−カルボン酸エチル４．２ｇ（２６．６ｍｍｏｌ）、トリエチルアミン７．４ｍｌ（５３．２ｍｍｏｌ）をキシレン１００ｍｌ中１３０℃で２４時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ２．９５ｇ（１２．６ｍｍｏｌ） 収率 ４７％
MS(ESI,m/z)235(MH+)
H-NMR(CDCl3)δ1.25(3H,t),1.71-1.85(2H,m),2.00(2H,d),2.50-2.60(1H,m),2.90(2H,t),3.81(2H,d),4.20(2H,q),6.66(2H,d),8.26(2H,d)
工程２
１−（４−ピリジル）−ピペリジン−４−カルボン酸 塩酸塩の合成
１−（４−ピリジル）−ピペリジン−４−カルボン酸エチル２．９５ｇ（１２．６ｍｍｏｌ）をジオキサン１００ｍｌ中撹拌し、１規定塩酸５０ｍｌを加え、９５℃で２０時間撹拌後、溶媒を減圧留去して表題化合物を得た。
収量 ３．２１ｇ（１１．５ｍｍｏｌ） 収率 ９１％
MS(ESI,m/z)207(MH+)
H-NMR(DMSO-d6)δ1.54(2H,t),1.90(2H,d),2.60-2.70(1H,m),3.30(2H,t),4.10(2H,d),7.19(2H,d),8.20(2H,d)
工程３
Ｎ−［２−（３−シアノフェノキシ）エチル］−１−（４−ピリジル）−ピペリジン−４−カルボキシアミドの合成
１−（４−ピリジル）−ピペリジン−４−カルボン酸 塩酸塩４１２ｍｇ（１．４８ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル３５０ｍｇ（１．７７ｍｍｏｌ）、トリエチルアミン０．２５ｍｌ（１．７７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２４０ｍｇ（１．７７ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３４０ｍｇ（１．７７ｍｍｏｌ）をジメチルホルムアミド３ｍｌ中、室温下一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ４７０ｍｇ（１．３４ｍｍｏｌ） 収率 ９１％
MS(ESI,m/z)351(MH+)
H-NMR(DMSO-d6)δ1.52(2H,dd),1.68(2H,d),2.38-2.45(1H,m),2.80(2H,t),3.40(2H,dd),3.90(2H,d),4.08(2H,t),6.80(2H,d),7.31(1H,d),7.40(1H,d),7.42(1H,s),7.51(1H,t),8.09(1H,t),8.13(2H,d)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−１−（４−ピリジル）ピペリジン−４−カルボキシアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−１−（４−ピリジル）−ピペリジン−４−カルボキシアミド４６０ｍｇ（１．３１ｍｍｏｌ）に塩化水素を３０％含む（ｗ／ｖ）エタノール１０ｍｌを加えて室温で７日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１０ｍｌに溶解して室温で３１時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ４０２ｍｇ（０．６７５ｍｍｏｌ） 収率 ５２％
MS(ESI,m/z)368(MH+)
H-NMR(DMSO-d6)δ1.57(2H,dd),1.82(2H,dd),2.51-2.60(1H,m),3.10(2H,t),3.40(2H,t),4.09(2H,t),4.23(2H,d),7.18(2H,d),7.25(1H,d),7.20(1H,s),7.40(1H,d),7.57(1H,t),8.02(2H,t),9.17(4H,t)
実施例２５
４−ベンゾイル−Ｎ−［２−（３−アミジノフェノキシ）エチル］ベンズアミド トリフルオロ酢酸塩の合成
４−ベンゾイル安息香酸２５７ｍｇ（１．１４ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．４８ｍｌ（３．４２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２４０ｍｇ（１．２５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１６９ｍｇ（１．２５ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２２６ｍｇ（１．１４ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ２０ｍｇ（０．０４ｍｍｏｌ） 収率 ４％
MS(ESI,m/z)388(MH+)
H-NMR(DMSO-d6)δ3.68(2H,dt),4.13(2H,t),7.27-7.44(4H,m),7.54(1H,dd),7.57(1H,d),7.59(2H,d),7.75(2H,d),7.81(2H,d),8.01(1H,d),8.91(1H,t),9.10(2H,br),9.29(2H,br)
実施例２６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−ジメチルアミノベンズアミド トリフルオロ酢酸塩の合成
４−ジメチルアミノ安息香酸２０４ｍｇ（１．２４ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．５２ｍｌ（３．７２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２６０ｍｇ（１．３６ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１８４ｍｇ（１．３６ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２４６ｍｇ（１．２４ｍｍｏｌ）を加え、１８時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ３００ｍｇ（０．６８ｍｍｏｌ） 収率 ５５％
MS(ESI,m/z)327(MH+)
H-NMR(DMSO-d6)δ2.96(6H,s),3.62(2H,dt),4.17(2H,t),6.70(2H,d),7.32-7.43(3H,m),7.54(1H,dd),7.74(2H,d),8.36(1H,t),9.05(2H,br),9.28(2H,br)
実施例２７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−３−（２−アミノエトキシ）ベンズアミジン 三トリフルオロ酢酸塩の合成
３−（２−アミノエトキシ）ベンゾニトリル１．７５ｇ（８．８４ｍｍｏｌ）に塩化水素を３０％含む（ｗ／ｖ）エタノール１０ｍｌを加えて室温で２２時間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１０ｍｌに溶解して室温で３１時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １３４ｍｇ（０．１９５ｍｍｏｌ） 収率 ２．２％
MS(ESI,m/z)342(MH+)
H-NMR(DMSO-d6)δ3.20-3.23(2H,m),3.81-3.85(2H,t),4.24(2H,dd),4.38(2H,dd),7.25-7.40(4H,m),7.50-7.60(4H,m),8.18(2H,brs),9.60(4H,t)
実施例２８
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−ベンジルベンズアミド トリフルオロ酢酸塩の合成
４−ベンゾイル安息香酸７８０ｍｇ（３．４５ｍｍｏｌ）を酢酸１０ｍｌに溶解させ、パラジウム−炭素１００ｍｇ、濃硫酸０．１ｍｌを加え、中圧水素存在下で１８時間撹拌した。溶媒留去後、反応液を水で希釈し、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．７３ｍｌ（５．２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２２０ｍｇ（１．１５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１５５ｍｇ（１．１５ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２０６ｍｇ（１．０４ｍｍｏｌ）を加え、１８時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様にして表題化合物を得た。
収量 １５０ｍｇ（０．３１ｍｍｏｌ） 収率 ９％
MS(ESI,m/z)374(MH+)
H-NMR(DMSO-d6)δ3.65(2H,dt),3.99(2H,s),4.20(2H,t),7.15-7.41(10H,m),7.53(1H,dd),7.78(2H,d),8.66(1H,t),9.14(2H,br),9.27(2H,br)
実施例２９
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペラジン−１−カルボニル）ベンズアミド 二トリフルオロ酢酸塩および
４−［Ｎ−［２−（３−アミジノフェノキシ）エチル］カルバモイル］安息香酸エチルエステル 二トリフルオロ酢酸塩の合成
工程１
４−（４−メトキシカルボニルベンゾイル）ピペラジン−１−カルボン酸 ｔ−ブチルの合成 ピペラジン−１−カルボン酸 ｔ−ブチル４．９３ｇ（２６．５ｍｍｏｌ）、トリエチルアミン４．８ｍｌ（３４．５ｍｍｏｌ）をジメチルホルムアミド５０ｍｌ中氷冷下撹拌し、そこへテレフタル酸モノメチルエステルクロライド５．２５ｇ（２６．５ｍｍｏｌ）をゆっくりと加え１６時間撹拌した。室温に戻した後、反応液を１規定塩酸で希釈し、酢酸エチルで抽出し常法に従って処理し表題化合物を得た。
収量 ７．０８ｇ（２０．３ｍｍｏｌ） 収率 ７７％
MS(ESI,m/z)349(MH+)
H-NMR(CDCl3)δ1.47(9H,s),3.25-3.60(6H,m),3.60-3.80(2H,m),3.94(3H,s),7.46(2H,d),8.09(2H,d)
工程２
４−（４−カルボキシベンゾイル）ピペラジン−１−カルボン酸 ｔ−ブチルの合成
４−（４−メトキシカルボニルベンゾイル）ピペラジン−１−カルボン酸 ｔ−ブチル７．０８ｇ（２０．３ｍｍｏｌ）をメタノール４０ｍｌ、ＴＨＦ４０ｍｌ中撹拌し、１規定水酸化ナトリウム水溶液５１ｍｌ（５１ｍｍｏｌ）を加え、８０℃で２０分撹拌した。反応液を減圧留去後、１規定 塩酸を加え酢酸エチルで抽出し常法に従い表題化合物を得た。
収量６．７８ｇ（２０．３ｍｍｏｌ） 収率 １００％
MS(ESI,m/z)335(MH+)
H-NMR(CDCl3)δ1.41(9H,s),3.20-3.50(6H,m),3.52-3.70(2H,m),7.49(2H,d),8.01(2H,d)
工程３
４−［４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］ベンゾイル］ピペラジン−１−カルボン酸 ｔ−ブチルの合成
４−（４−カルボキシベンゾイル）ピペラジン−１−カルボン酸 ｔ−ブチル１．６０ｇ（４．８ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル１．５８ｇ（８．０ｍｍｏｌ）、トリエチルアミン１．６７ｍｌ（１２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール６５０ｍｇ（４．８ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩９２０ｍｇ（４．８ｍｍｏｌ）をジメチルホルムアミド２０ｍｌ中、室温下一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量１．４４ｇ（３．０２ｍｍｏｌ） 収率 ６３％
MS(ESI,m/z)479(MH+)
H-NMR(CDCl3)δ1.47(9H,s),3.20-3.60(6H,m),3.62-3.80(2H,m),3.91(2H,t),4.20(2H,t),6.60(1H,brs),7.15(1H,d),7.18(1H,s),7.28(1H,d),7.39(1H,t),7.49(2H,d),7.82(2H,d)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペラジン−１−カルボニル）ベンズアミド 二トリフルオロ酢酸塩および
４−［Ｎ−［２−（３−アミジノフェノキシ）エチル］カルバモイル］安息香酸エチルエステル 二トリフルオロ酢酸塩の合成
４−［４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］ベンゾイル］−ピペラジン−１−カルボン酸 ｔ−ブチル１．４４ｇ（３．０２ｍｍｏｌ）を４規定塩化水素を含むジオキサン５ｍｌ中撹拌し、そこへ塩化水素を３０％含む（ｗ／ｖ）エタノール５ｍｌを加えて室温で３日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液５ｍｌに溶解して室温で２２時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペラジン−１−カルボニル）ベンズアミド 二トリフルオロ酢酸塩
収量 １４５ｍｇ（０．２３ｍｍｏｌ） 収率 ７．７％
MS(ESI,m/z)396(MH+)
H-NMR(DMSO-d6)δ3.10-3.23(6H,m),3.40-3.80(2H,m),3.65(2H,t),4.23(2H,t)7.33(1H,d),7.38(2H,d),7.50(1H,d),7.55(2H,d),7.95(2H,d),8.86(1H,t),9.00(2H,brs),9.20(4H,d)
４−［Ｎ−［２−（３−アミジノフェノキシ）エチル］カルバモイル］安息香酸エチルエステル 二トリフルオロ酢酸塩
MS(FAB,m/z)356(MH+)
H-NMR(DMSO-d6)δ1.34(3H,t),3.68(2H,dt),4.23(2H,t),4.38(2H,q),7.35-7.40(3H,m),7.51(1H,t),7.97(2H,d),8.02(2H,d),8.92(1H,t),9.10(2H,br),9.26(2H,br)
実施例３０
４−（４−アセトイミドイルピペラジン−１−カルボニル）−Ｎ−［２−（３−アミジノフェノキシ）エチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペラジン−１−カルボニル）ベンズアミド 二トリフルオロ酢酸塩５９７ｍｇ（１．５１ｍｍｏｌ）をエタノール１２ｍｌに溶解し、トリエチルアミン１ｍｌ（７．８ｍｍｏｌ）、エチル アセトイミダート 塩酸塩３８０ｍｇ（０．７６４ｍｍｏｌ）を加え室温で２日撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ２３．３ｍｇ（０．０３５ｍｍｏｌ） 収率 ２．３％
MS(ESI,m/z)437(MH+)
H-NMR(DMSO-d6)δ2.30(3H,brs),3.10-3.25(2H,m),3.40-3.80(8H,m),4.24(2H,t),7.30(1H,d),7.39(2H,d),7.52(1H,d),7.55(2H,d),7.95(2H,d),8.70(1H,t),8.87(2H,brs),9.22(4H,d)
実施例３１
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−アミノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−アミノベンズアミドの合成
３−（２−アミノエトキシ）ベンゾニトリル 塩酸塩４．００ｇ（２０．４ｍｍｏｌ）をジメチルホルムアミド５０ｍｌに溶解し、トリエチルアミン６．２ｍｌ（４３．８ｍｍｏｌ）、パラアミノ安息香酸２．００ｇ（１４．６ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１．９８ｇ（１４．６ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２．８０ｇ（１４．６ｍｍｏｌ）を０℃で加え、室温で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理したのちシリカゲルクロマトグラフィーで精製して表題化合物を得た。
収量 １．６９ｇ（６．０１ｍｍｏｌ） 収率 ２９％
MS(ESI,m/z)282(MH+)
H-NMR(DMSO-d6)δ3.58(2H,q),4.15(2H,t),5.61(2H,br),6.54(2H,d),7.32(1H,d),7.38(1H,d),7.44(1H,s),7.58(2H,d),7.95(1H,s),8.19(1H,t)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−アミノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−アミノベンズアミド１１０ｍｇ（０．３９ｍｍｏｌ）を出発原料とし、実施例１工程６と同様の操作に従い表題化合物を得た。
収量 ４５．５ｍｇ（０．０８７ｍｍｏｌ） 収率 ２２％
MS(ESI,m/z)299(MH+)
H-NMR(DMSO-d6)δ3.21(2H,br),4.38(2H,dd),7.19(1H,s),7.34(1H,d),7.36(1H,s),7.42-7.60(5H,m),8.42(3H,br),9.34(2H,br),9.54(2H,br)
実施例３２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（フェニルメタンスルホニルアミノ）ベンズアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（フェニルメタンスルホニルアミノ）ベンズアミドの合成
４−アミノ−Ｎ−［２−（３−シアノフェノキシ）エチル］ベンズアミド６７０ｍｇ（２．３８ｍｍｏｌ）をジメチルホルムアミド１０ｍｌに溶解し、ジイソプロピルエチルアミン０．４２ｍｌ（２．３８ｍｍｏｌ）、α−トルエンスルホニルクロリド４５４ｍｇ（２．３８ｍｍｏｌ）を０℃で加え、１３時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し、表題化合物を得た。収量２００ｍｇ（０．４６ｍｍｏｌ） 収率 １９％
MS(ESI,m/z)436(MH+)
H-NMR(CDCl3)δ3.70(2H,t),4.10(2H,t),4.79(2H,s),7.10-7.19(2H,m),7.20-7.28(2H,m),7.30-7.40(5H,m),7.48(2H,d),7.51(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（フェニルメタンスルホニルアミノ）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（フェニルメタンスルホニルアミノ）ベンズアミド２６１ｍｇ（０．６ｍｍｏｌ）に塩化水素を３０％含む（ｗ／ｖ）エタノール１０ｍｌを加えて室温で３日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１０ｍｌに溶解して室温で３１時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ７１．７ｍｇ（０．１２７ｍｍｏｌ） 収率 ２１％
MS(ESI,m/z)453(MH+)
H-NMR(DMSO-d6)δ3.69(2H,t),4.19(2H,t),4.53(2H,s),7.20-7.40(11H,m),7.84(2H,d),8.64(1H,t),9.10(4H,d)
実施例３３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−フェノキシベンズアミド トリフルオロ酢酸塩の合成
４−フェノキシ安息香酸２９６ｍｇ（１．４ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．５６ｍｌ（４．２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２９５ｍｇ（１．５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２０８ｍｇ（１．５ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２７７ｍｇ（１．４ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。収量 ３６０ｍｇ（０．７４ｍｍｏｌ） 収率 ５３％
MS(ESI,m/z)376(MH+)
H-NMR(DMSO-d6)δ3.67(2H,dt),4.21(2H,t),7.01(2H,d),7.07(2H,d),7.18(1H,d),7.30-7.48(5H,m),7.53(1H,dd),7.88(2H,d),8.70(1H,t),9.23(2H,br),9.29(2H,br)
実施例３４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−２−［Ｎ−メチル−Ｎ−（ピリジン−４−イル）アミノ］アセトアミド 二トリフルオロ酢酸塩の合成
工程１
［Ｎ−メチル−Ｎ−（ピリジン−４−イル）アミノ］酢酸エチルの合成
４−クロロピリジン１７ｇ（１１３ｍｍｏｌ）、（メチルアミノ）酢酸エチル１７ｇ（１１１ｍｍｏｌ）、トリエチルアミン４７ｍｌ（３３３ｍｍｏｌ）をキシレン３５０ｍｌ中１３０℃で２４時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 １．２８ｇ（６．５９ｍｍｏｌ） 収率 ６％
H-NMR(CDCl3)δ1.26(3H,t),3.09(2H,s),4.17(3H,s),4.24(2H,q),6.49(2H,d),8.25(2H,d)
工程２
［Ｎ−メチル−Ｎ−（ピリジン−４−イル）アミノ］酢酸 塩酸塩の合成
［Ｎ−メチル−Ｎ−（ピリジン−４−イル）アミノ］酢酸エチル１．２８ｇ（６．６０ｍｍｏｌ）をジオキサン３０ｍｌ中撹拌し、１規定塩酸２６ｍｌを加え、９５℃で２０時間撹拌後、溶媒を減圧留去して表題化合物を得た。
収量 １．２４ｇ（５．１９ｍｍｏｌ） 収率 ７９％
H-NMR(DMSO-d6)δ3.19(3H,s),4.48(2H,s),7.03(2H,brs),8.30(2H,brs)
工程３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−２−［Ｎ−メチル−Ｎ−（ピリジン−４−イル）アミノ］アセトアミド 二トリフルオロ酢酸塩の合成
［Ｎ−メチル−Ｎ−（ピリジン−４−イル）アミノ］酢酸 塩酸塩３００ｍｇ（１．２６ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル３００ｍｇ（１．５１ｍｍｏｌ）、トリエチルアミン０．２１ｍｌ（１．５１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２０５ｍｇ（１．５１ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２９０ｍｇ（１．５１ｍｍｏｌ）をジメチルホルムアミド１．３ｍｌ中、室温下一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。この粗製物を４規定塩化水素を含むジオキサン２ｍｌ中撹拌し、そこへ塩化水素を３０％含む（ｗ／ｖ）エタノール２ｍｌを加えて室温で７日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液２ｍｌに溶解して室温で３１時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １８５ｍｇ（０．２８１ｍｍｏｌ） 収率 ２２％
MS(ESI,m/z)328(MH+)
H-NMR(DMSO-d6)δ3.24(3H,s),3.50(2H,t),4.10(2H,t),4.30(2H,s),6.99(2H,brs),7.31(1H,d),7.33(1H,s),7.40(1H,d),7.57(1H,t),8.25(2H,brs),8.56(1H,t),9.38(4H,d)
実施例３５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピリジン−４−イル）アミノ］ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−［（ピリジン−４−イル）アミノ］安息香酸エチルの合成
４−クロロピリジン４．５７ｇ（３１ｍｍｏｌ）、４−アミノ安息香酸エチル５．０３ｇ（３１ｍｍｏｌ）をキシレン１００ｍｌに溶解させ、トリエチルアミン１２．７ｍｌ（９２ｍｍｏｌ）を加え５０時間加熱還流した。溶媒留去後、反応液を水で希釈し、ジクロロメタンにて抽出した。飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ３６０ｍｇ（１．４９ｍｍｏｌ） 収率 ５％
H-NMR(CDCl3)δ1.40(3H,t),4.37(2H,q),6.95(2H,dd),7.19(2H,dd),8.03(2H,dd),8.38(2H,dd)
工程２
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（ピリジン−４−イル）アミノ］ベンズアミドの合成
４−［（ピリジン−４−イル）アミノ］安息香酸エチル１８０ｍｇ（０．７４３ｍｍｏｌ）を濃塩酸５ｍｌに溶解させ、７０℃で１５時間撹拌した。溶媒を留去後、ジクロロメタン５ｍｌに溶解させ、トリエチルアミン０．２３ｍｌ（１．６４ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１５６ｍｇ（０．８２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２０８ｍｇ（０．８２ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル臭化水素酸塩１９９ｍｇ（０．８２ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ９９ｍｇ（０．２７ｍｍｏｌ） 収率 ３７％
H-NMR(CD3OD)δ3.78(2H,dt),4.23(2H,t),7.06(1H,dd),7.25-7.40(6H,m),7.85(2H,dd),8.19(2H,dd)
工程３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピリジン−４−イル）アミノ］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（ピリジン−４−イル）アミノ］ベンズアミド９５ｍｇ（０．２７ｍｍｏｌ）を実施例１工程６と同様の操作に従って表題化合物を得た。収量 ５１ｍｇ（０．０８ｍｍｏｌ） 収率 ３２％
MS(ESI,m/z)376(MH+)
H-NMR(DMSO-d6)δ3.68(2H,dt),4.24(2H,t),7.24(2H,d),7.30-7.37(2H,m),7.39-7.48(3H,m),7.53(1H,dd),7.98(2H,d),8.12-8.26(1H,m),8.34(2H,d),8.80-8.89(1H,m),9.16(2H,br),9.33(2H,br)
実施例３６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ−メチルカルバモイル）ベンズアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ−メチルカルバモイル）ベンズアミドの合成
４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］安息香酸１５０ｍｇ（０．４８ｍｍｏｌ）、クロロ蟻酸エチル５２ｍｇ（０．４８ｍｍｏｌ）、トリエチルアミン０．５ｍｌ（過剰量）、４０％モノメチルアミン水溶液３ｍｌを用いて実施例３工程２と同様にして表題化合物を得た。
収量 ８７ｍｇ（０．２７ｍｍｏｌ） 収率 ５６％
H-NMR(CDCl3)δ3.05(3H,d),3.90(2H,dt),4.20(2H,t),6.20(1H,br),6.61(1H,br),7.15(1H,d),7.17(1H,s),7.27(1H,d),7.39(1H,t),7.83(4H,s)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（Ｎ−メチルカルバモイル）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（Ｎ−メチルカルバモイル）ベンズアミド８３ｍｇ（０．２６ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ６８ｍｇ（０．１５ｍｍｏｌ） 収率 ５８％
MS(ESI,m/z)341(MH+)
H-NMR(DMSO-d6)δ2.80(3H,d),3.70(2H,dt),4.20(2H,t),7.34(1H,d),7.39(1H,d),7.40(1H,s),7.54(1H,t),7.88-7.94(4H,m),8.54(1H,d),8.82(1H,t),9.05(2H,br),9.28(2H,br)
実施例３７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−フェニルベンズアミド トリフルオロ酢酸塩の合成
４−フェニル安息香酸１３２ｍｇ（０．６７ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．２８ｍｌ（２．０ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１４１ｍｇ（０．７３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール５９ｍｇ（０．５９ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩１３２ｍｇ（０．６７ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。収量 ３０ｍｇ（０．０８ｍｍｏｌ） 収率 ８％
MS(ESI,m/z)360(MH+)
H-NMR(DMSO-d6)δ3.89(2H,dt),4.25(2H,t),7.31-7.45(3H,m),7.48(2H,d),7.52(1H,d),7.54(1H,dd),7.73(2H,d),7.78(2H,d),7.98(2H,d),8.82(1H,t),9.15(2H,br),9.33(2H,br)
実施例３８
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−シクロヘキシルベンズアミド トリフルオロ酢酸塩の合成
４−シクロヘキシル安息香酸１３６ｍｇ（０．６７ｍｍｏｌ）、ジメチルホルムアミド５ｍｌ、Ｎ−メチルモルホリン０．０７ｍｌ（１．３４ｍｍｏｌ）中に氷冷下クロロギ酸エチル０．１０ｍｌ（０．６７ｍｍｏｌ）を加え３０分撹拌した。同温下、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩１３２ｍｇ（０．６７ｍｍｏｌ）を加え、室温に戻して１時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定塩酸、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ４０ｍｇ（０．０８ｍｍｏｌ） 収率 １２％
MS(ESI,m/z)366(MH+)
H-NMR(DMSO-d6)δ1.18-1.51(5H,m),1.45(9H,s),1.65-1.78(5H,m),2.52-2.63(1H,m),3.65(2H,dt),4.21(2H,t),7.25-7.37(3H,m),7.39(2H,d),7.54(1H,dd),7.79(2H,d),8.68(1H,t),9.15(2H,br),9.34(2H,br)
実施例３９
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペラジン−１−スルホニル）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（４−メトキシカルボニルベンゼンスルホニル）−ピペラジン−１−カルボン酸 ｔ−ブチルの合成
ピペラジン−１−カルボン酸 ｔ−ブチル１０．６７ｇ（５７．３ｍｍｏｌ）をジメチルホルムアミド１８０ｍｌに溶解し、ジイソプロピルエチルアミン１０ｍｌ（５７．３ｍｍｏｌ）、およびジメチルホルムアミド２０ｍｌに溶解した４−ヨード−ベンゼンスルホニルクロリド１７．３ｇ（５７．３ｍｍｏｌ）を０℃で加え、５時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し４−（４−ヨードベンゼンスルホニル）−ピペラジン−１−カルボン酸 ｔ−ブチル粗製物を得た。この粗製物をジメチルホルムアミド１５０ｍｌに溶解し、酢酸パラジウム（ＩＩ）７５０ｍｇ（３．５ｍｍｏｌ）、メタノール５５ｍｌ（１．３９ｍｏｌ）、トリエチルアミン１９ｍｌ（１３９ｍｍｏｌ）を加え一酸化炭素存在下２３時間９０℃で加熱し、撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物の粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製した。
収量４．３０ｇ（１１．２ｍｍｏｌ） 収率 ２０％
H-NMR(CDCl3)δ1.42(9H,s),2.98(4H,t),3.51(4H,t),3.97(3H,s),7.82(2H,d),8.20(2H,d)
工程２
４−（４−カルボキシベンゼンスルホニル）−ピペラジン−１−カルボン酸 ｔ−ブチルの合成 ４−（４−メトキシカルボニルベンゼンスルホニル）−ピペラジン−１−カルボン酸 ｔ−ブチル４．３０ｇ（１１．２ｍｍｏｌ）をメタノール１５ｍｌ、ＴＨＦ１５ｍｌ中撹拌し、１規定水酸化ナトリウム水溶液１７ｍｌを加え、一晩６０℃で撹拌した。反応液を減圧留去後、１規定 塩酸を加え酢酸エチルを抽出溶媒とし、常法に従って処理し、表題化合物を得た。
収量１．４１ｇ（３．８ｍｍｏｌ） 収率 ３４％
MS(ESI,m/z)398(M+Na+)
H-NMR(CDCl3)δ1.41(9H,s),3.02(4H,t),3.52(4H,t),7.84(2H,d),8.24(2H,d)
工程３
４−［４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］ベンゼンスルホニル］−ピペラジン−１−カルボン酸 ｔ−ブチルの合成
（４−カルボキシベンゼンスルホニル）ピペラジン−１−カルボン酸 ｔ−ブチル１．４１ｇ（３．７９ｍｍｏｌ）をジメチルホルムアミド中撹拌し、氷冷下トリエチルアミン１．３ｍｌ（９．２５ｍｍｏｌ）、クロロ蟻酸エチル０．３８ｍｌ（３．９５ｍｍｏｌ）を加え５分間撹拌した後、３−（２−アミノエトキシ）ベンゾニトリル１．０２ｇ（４．６１ｍｍｏｌ）を加えた。室温に戻して２時間撹拌した後、１規定塩酸で希釈し酢酸エチルで抽出、常法に従って処理し表題化合物を得た。
収量 １．８８ｇ（３．６６ｍｍｏｌ） 収率 ９７％
MS(ESI,m/z)537(M+Na+)
H-NMR(CDCl3)δ1.40(9H,s),2.97(4H,t),3.49(4H,t),3.91(2H,dd),4.19(2H,t),7.03(1H,t),7.14(1H,d),7.17(1H,s),7.27(1H,d),7.38(1H,d),7.78(2H,d),7.98(2H,d)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペラジン−１−スルホニル）ベンズアミド 二トリフルオロ酢酸塩の合成
［４−［Ｎ−［２−（３−シアノフェノキシ）エチル］カルバモイル］ベンゼンスルホニル］ピペラジン−１−カルボン酸 ｔ−ブチル１．８８ｇ（３．６６ｍｍｏｌ）を４規定塩化水素を含むジオキサン０．９２ｍｌ（３．６６ｍｍｏｌ）中撹拌し、そこへ塩化水素を３０％含む（ｗ／ｖ）エタノール４ｍｌを加えて室温で６日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液５ｍｌに溶解して室温で１７時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ７３６ｍｇ（１．１２ｍｍｏｌ） 収率 ３１％
MS(ESI,m/z)432(MH+)
H-NMR(DMSO-d6)δ3.12(4H,d),3.20(4H,d),3.70(2H,dd),4.22(2H,t),7.32(1H,d),7.38(1H,s),7.40(1H,d),7.54(1H,t),7.90(2H,d),8.14(2H,d),8.60(1H,brs),8.95(1H,brs),9.15(4H,d)
実施例４０
４−（４−アセトイミドイルピペラジン−１−スルホニル）−Ｎ−［２−（３−アミジノフェノキシ）エチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（ピペラジン−１−スルホニル）ベンズアミド 二トリフルオロ酢酸塩２４０ｍｇ（０．３６４ｍｍｏｌ）をエタノール３ｍｌに溶解し、トリエチルアミン０．２７ｍｌ（１．８９ｍｍｏｌ）、エチル アセトイミダート 塩酸塩９５ｍｇ（０．７６４ｍｍｏｌ）を加え室温で６時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １１３ｍｇ（０．１６１ｍｍｏｌ） 収率 ４４％
MS(ESI,m/z)473(MH+)
H-NMR(DMSO-d6)δ2.18(3H,s),3.05-3.18(4H,m),3.58-3.68(4H,m),3.75(2H,t),4.44(2H,t),7.31(1H,d),7.39(1H,s),7.41(1H,d),7.54(1H,t),7.88(2H,d),8.12(2H,d),8.68(1H,s),9.05(1H,t),9.28(4H,d)
実施例４１
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピリジン−４−イル）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（４−ヨードベンジル）ピリジンの合成
４−ベンジルピリジン５．０ｇ（３０ｍｍｏｌ）を酢酸３０ｍｌに溶解させ、濃硫酸３．５３ｍｌ（６５ｍｍｏｌ）、ヨウ素２．９９ｇ（１１．８ｍｍｏｌ）、ヨウ素酸ナトリウム１．１７ｇ（５．９ｍｍｏｌ）を加え、７０℃で２０時間撹拌した。冷却後、メタ過ヨウ素酸ナトリウム０．１５ｇを加え、減圧留去した。水を加え、ジクロロメタン洗浄し、１規定水酸化ナトリウムを加え、ジクロロメタン抽出を２回した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ２．７ｇ（９．２ｍｍｏｌ） 収率 ３１％
H-NMR(CDCl3)δ3.91(2H,s),6.92(2H,d),7.07(2H,d),7.64(2H,d),8.50(2H,d)
工程２
４−［（ピリジン−４−イル）メチル］安息香酸メチルの合成
４−（４−ヨードベンジル）ピリジン１．０３ｇ（３．４９ｍｍｏｌ）をジメチルホルムアミド１５ｍｌに溶解させ、酢酸パラジウム３９ｍｇ（０．１８ｍｍｏｌ）、トリエチルアミン０．９７ｍｌ（６．９８ｍｍｏｌ）、メタノール２．８２ｍｌ（６９．８ｍｍｏｌ）を加え、一酸化炭素存在下、７０℃で６時間撹拌した。反応液を水で希釈し、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ６３０ｍｇ（２．７８ｍｍｏｌ） 収率 ７９％
H-NMR(CDCl3)δ3.91(3H,s),4.02(2H,s),7.08(2H,d),7.24(2H,d),7.98(2H,d),8.51(2H,dd)
工程３
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（ピリジン−４−イル）メチル］ベンズアミドの合成
４−［（ピリジン−４−イル）メチル］安息香酸メチル２６２ｍｇ（１．１５ｍｍｏｌ）を濃塩酸５ｍｌに溶解させ、７０℃で１５時間撹拌した。溶媒を留去して得られた残留物をジクロロメタン５ｍｌに溶解させ、トリエチルアミン０．２４ｍｌ（１．７３ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２４３ｍｇ（１．２７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１７２ｍｇ（１．２７ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩３０８ｍｇ（１．２７ｍｍｏｌ）を加え、１５時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ３２０ｍｇ（０．９０ｍｍｏｌ） 収率 ７８％
H-NMR(CDCl3)δ3.89(2H,dt),4.02(2H,s),4.18(2H,t),6.46-6.57(1H,m),7.16(2H,br),7.25(2H,d),7.27(2H,d),7.39(1H,dd),7.74(2H,d),8.51(2H,dd)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピリジン−４−イル）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（ピリジン−４−イル）メチル］ベンズアミド２１８ｍｇ（０．６１ｍｍｏｌ）を出発原料とし、実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １７０ｍｇ（０．４５ｍｍｏｌ） 収率 ７４ ％
MS(ESI,m/z)375(MH+)
H-NMR(DMSO-d6)δ3.65(2H,dt),4.20(2H,s),4.21(2H,t),7.22-7.43(5H,m),7.47(1H,dd),7.60(2H,d),7.83(2H,dd),8.65(3H,br),9.08(2H,br),9.28(2H,br)
実施例４２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピペリジン−４−イリデン）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（ジエトキシホスホリルメチル）安息香酸メチルの合成
４−（ブロモメチル）安息香酸メチル２．２９ｇ（１０ｍｍｏｌ）にトリエチルホスファイト６．６４ｇ（４０ｍｍｏｌ）を加え、１５０℃で１９時間撹拌した。反応液をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ２．６ｇ（９ｍｍｏｌ） 収率 ９０％
H-NMR(CDCl3)δ1.25(6H,t),3.20(2H,d),4.02(4H,dq),7.39(2H,d),8.00(2H,d)
工程２
４−［［１−（ｔ−ブトキシカルボニル）ピペリジン−４−イリデン］メチル］安息香酸メチルの合成
４−ピペリドン１．０ｇ（５．０ｍｍｏｌ）にトリエチルアミン２．７ｍｌ（２０．０ｍｍｏｌ）、ジ−ｔ−ブチルカルボネート１．８４ｇ（８．４５ｍｍｏｌ）、ジクロロメタン３０ｍｌを加え１９時間撹拌した。反応液を水で希釈し、ジクロロメタンにて抽出した。有機層を１規定塩酸、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去し、１−ｔ−ブトキシカルボニル−４−ピペリドンを得た。氷冷下、水素化ナトリウム２４１ｍｇ（６．０ｍｍｏｌ）にテトラヒドロフラン８０ｍｌ、４−（ジエトキシホスホリルメチル）安息香酸メチルを加え、３０分撹拌後室温に戻して３０分撹拌した。先ほど得られた１−ｔ−ブトキシカルボニル−４−ピペリドン粗製物を加え２０時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 １．２６ｇ（３．８ｍｍｏｌ） 収率 ７６％
H-NMR(CDCl3)δ1.48(9H,s),2.38(2H,dd),2.44(2H,dd),3.42(2H,dd),3.53(2H,dd),3.89(3H,s),6.39(1H,br),7.24(2H,d),7.98(2H,d)
工程３
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（１−ｔ−ブトキシカルボニルピペリジン−４−イリデン）メチル］ベンズアミドの合成
４−［（１−ｔ−ブトキシカルボニルピペリジン−４−イリデン）メチル］安息香酸メチル３３１ｍｇ（１．０ｍｍｏｌ）に１規定水酸化ナトリウム６ｍｌ、エタノール１８ｍｌを加え、１８時間撹拌した。反応液を１規定塩酸で酸性にした後、有酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物に氷冷下、ジメチルホルムアミド５ｍｌ、Ｎ−メチルモルホリン０．２２ｍｌ（２．０ｍｍｏｌ）、クロロギ酸エチル０．１０ｍｌ（１．０ｍｍｏｌ）を加え３０分撹拌した。同温下、３−（２−アミノエトキシ）ベンゾニトリル臭化水素酸塩２４３ｍｇ（１．０ｍｍｏｌ）を加え、室温に戻して１時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定塩酸、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ３０９ｍｇ（０．６７ｍｍｏｌ） 収率 ６７％
H-NMR(CDCl3)δ1.48(9H,s),2.35(2H,dd),2.44(2H,dd),3.41(2H,dd),3.52(2H,dd),3.89(2H,dt),4.18(2H,t),6.37(1H,br),6.51-6.60(1H,m),7.17(1H,br),7.23-7.29(1H,m),7.39(1H,dt),7.74(2H,d)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピペリジン−４−イリデン）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（１−ｔ−ブトキシカルボニルピペリジン−４−イリデン）メチル］ベンズアミド２３０ｍｇ（０．５０ｍｍｏｌ）を出発原料とし、実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １９０ｍｇ（０．３１ｍｍｏｌ） 収率 ６３％
MS(ESI,m/z)379(MH+)
H-NMR(DMSO-d6)δ2.42-2.68(4H,m),2.99-3.24(4H,m),3.68(2H,dt),4.22(2H,t),6.53(1H,s),7.24-7.43(6H,m),7.56(1H,t),7.88(2H,d),8.77(3H,br),9.17(2H,br),9.30(2H,br)
実施例４３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピペリジン−４−イル）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（１−ｔ−ブトキシカルボニルピペリジン−４−イル）メチル］ベンズアミドの合成
４−［（１−ｔ−ブトキシカルボニルピペリジン−４−イリデン）メチル］安息香酸メチル４３４ｍｇ（１．３１ｍｍｏｌ）に、１０％パラジウム−炭素９５ｍｇ、メタノール２０ｍｌを加え、水素存在下１５時間撹拌した。セライト濾過後、溶媒を留去して得られた残留物に１規定水酸化ナトリウム４ｍｌ、エタノール６ｍｌを加え、１８時間撹拌した。反応液を１規定塩酸で酸性にした後、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物に氷冷下、ジメチルホルムアミド５ｍｌ、Ｎ−メチルモルホリン０．２２ｍｌ（２．０ｍｍｏｌ）、クロロギ酸エチル０．１０ｍｌ（１．０ｍｍｏｌ）を加え３０分撹拌した。同温下、３−（２−アミノエトキシ）ベンゾニトリル臭化水素酸塩２４３ｍｇ（１．０ｍｍｏｌ）を加え、室温に戻して１時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定塩酸、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ２９６ｍｇ（０．６４ｍｍｏｌ） 収率 ４９％
H-NMR(CDCl3)δ1.10-1.19(2H,m),1.45(9H,s),1.58-1.78(3H,m),2.59(2H,d),2.61-2.69(2H,m),3.89(2H,dt),4.00-4.13(2H,m),4.18(2H,t),6.46-6.55(1H,m),7.17(2H,br),7.18(2H,d),7.27(1H,dt),7.71(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピペリジン−４−イル）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（１−ｔ−ブトキシカルボニルピペリジン−４−イル）メチル］ベンズアミド２３０ｍｇ（０．５０ｍｍｏｌ）を原料とし、実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １９０ｍｇ（０．３１ｍｍｏｌ） 収率 ６３％
MS(ESI,m/z)381(MH+)
H-NMR(DMSO-d6)δ1.21-1.41(2H,m),1.62-1.74(2H,m),1.77-1.93(1H,m),2.59(2H,d),2.70-2.89(2H,m),3.05-3.32(2H,m),3.66(2H,dt),4.21(2H,t),7.28(2H,d),7.30-7.36(1H,m),7.37-7.43(2H,m),7.54(1H,dd)7.81(2H,d),8.18-8.36(1H,m),8.51-8.64(2H,m),8.68(1H,t),9.22(2H,br),9.29(2H,br)
実施例４４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（１−アセトイミドイルピペリジン−４−イリデン）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピペリジン−４−イリデン）メチル］ベンズアミド 二トリフルオロ酢酸塩９．９ｍｇ（０．０２ｍｍｏｌ）をエタノール２ｍｌに溶解させ、トリエチルアミン０．０２ｍｌ（０．１５ｍｍｏｌ）エチルアセトイミダート塩酸塩４ｍｇ（０．０３ｍｍｏｌ）を加え、１５時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ８．４ｍｇ（０．０１ｍｍｏｌ） 収率 ７９％
MS(ESI,m/z)420(MH+)
H-NMR(DMSO-d6)δ2.31(3H,s),2.54-2.66(3H,m),2.68-2.75(1H,m),3.55-3.66(4H,m),3.67(2H,dt),4.22(2H,t),6.50(H,br),7.29-7.44(5H,m),7.53(1H,dd)7.86(2H,d),8.56(1H,br),8.74(1H,t),9.16(1H,br),9.20(2H,br),9.28(2H,br)
実施例４５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（１−アセトイミドイルピペリジン−４−イル）メチル］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（ピペリジン−４−イリデン）メチル］ベンズアミド 二トリフルオロ酢酸塩１０ｍｇ（０．０２ｍｍｏｌ）をエタノール２ｍｌに溶解させ、トリエチルアミン０．０２ｍｌ（０．１５ｍｍｏｌ）エチルアセトイミダート塩酸塩４ｍｇ（０．０３ｍｍｏｌ）を用いて実施例４４と同様の操作に従って表題化合物を得た。
収量 ６ｍｇ（０．０１ｍｍｏｌ） 収率 ５６％
MS(ESI,m/z)422(MH+)
H-NMR(DMSO-d6)δ1.21-1.35(2H,m),1.59-1.62(2H,m),1.83-2.00(1H,m),2.24(3H,s),2.59(2H,d),2.94-3.20(2H,m),3.66(2H,dt),3.80-3.92(1H,m),3.96-4.08(2H,m),4.21(2H,t),7.24-7.43(5H,m),7.53(1H,dd)7.81(2H,d),8.48(1H,br),8.68(1H,t),9.03(1H,br),9.15(2H,br)9.28(2H,br)
実施例４６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（２−１Ｈ−イミダゾリル）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（２−１Ｈ−イミダゾリル）安息香酸 エチルエステルの合成
４−（２−イミダゾリン−２−イル）安息香酸 エチルエステル５００ｍｇ（２．３ｍｍｏｌ）、１０％パラジウム−炭素５００ｍｇをトルエン２０ｍｌ中、アルゴン雰囲気下９時間加熱環流した。反応液を酢酸エチルで希釈しセライト濾過後、濾液を濃縮し表題化合物を得た。
収量 ３３２ｍｇ（１．５ｍｍｏｌ） 収率 ６７％
H-NMR(CDCl3)δ1.40(3H,t),4.40(2H,q),7.20(2H,s),7.90(2H,d),8.10(2H,d)
工程２
４−（２−１Ｈ−イミダゾリル）安息香酸 塩酸塩の合成
４−（２−１Ｈ−イミダゾリル）安息香酸 エチルエステル１６０ｍｇ（０．７４ｍｍｏｌ）を塩酸４ｍｌおよび酢酸８ｍｌ中で加熱環流した。３時間後溶媒を留去し表題化合物を得た。
収量 １５７ｍｇ（０．７０ｍｍｏｌ） 収率 ９４％
H-NMR(DMSO-d6)δ7.82(2H,s),8.15(2H,d),8.25(2H,d)
工程３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（２−１Ｈ−イミダゾリル）ベンズアミド 二トリフルオロ酢酸塩の合成
４−（２−１Ｈ−イミダゾリル）安息香酸 塩酸塩１５５ｍｇ（０．７ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル 臭化水素酸塩１９５ｍｇ（０．８ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩１５３ｍｇ（０．８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール水和物（含水、８７％）１２４ｍｇ（０．８ｍｍｏｌ）、トリエチルアミン３００ｍｇ（３．０ｍｍｏｌ）をジクロロメタン中、室温から４０℃で２日間撹拌した。溶媒を留去し１規定水酸化ナトリウム水溶液を加え酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残留物をクロロホルムに懸濁して濾過を行い、濾取物を実施例１工程６と同様にして表題化合物を得た。
収量 ７８ｍｇ（０．１４ｍｍｏｌ） 収率 ２０％
MS(ESI,m/z)350(MH+)
H-NMR(DMSO-d6)δ3.70(2H,dt),4.23(2H,t),7.34(1H,d),7.40(1H,d),7.41(1H,s),7.54(1H,t),7.72(2H,s),8.06(2H,d),8.16(2H,d),8.96(1H,t),9.16(2H,br),9.32(2H,br)
実施例４７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−アセチルベンズアミド トリフルオロ酢酸塩の合成
４−アセチル安息香酸２２３ｍｇ（１．３６ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン０．９５ｍｌ（６．８０ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２８６ｍｇ（１．５０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２０２ｍｇ（１．５０ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２６９ｍｇ（１．３６ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １８８ｍｇ（０．５８ｍｍｏｌ） 収率 ４３％
MS(ESI,m/z)326(MH+)
H-NMR(DMSO-d6)δ2.62(3H,s),3.70(2H,dt),4.24(2H,t),7.31-7.42(3H,m),7.53(1H,dd),8.00(4H,dd),8.93(1H,br),9.11(2H,br),9.28(2H,br)
実施例４８
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−クロロベンズアミド トリフルオロ酢酸塩の合成
３−（２−アミノエトキシ）ベンゾニトリル塩酸塩２０５ｍｇ（１．０２ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、氷冷下、トリエチルアミン０．４４ｍｌ（３．１２ｍｍｏｌ）、４−クロロベンゾイルクロライド２１７ｍｇ（１．０４ｍｍｏｌ）を加え、３０分撹拌後、室温に戻して３時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を１規定塩酸、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １７０ｍｇ（０．３９ｍｍｏｌ） 収率 ３８％
MS(ESI,m/z)317(MH+)
H-NMR(DMSO-d6)δ3.69(2H,dt),4.24(2H,t),7.34(1H,dd),7.40(2H,br),7.54(1H,dd),7.86(2H,d),8.06(2H,d),8.99(1H,br),9.12(2H,br),9.28(2H,br)
実施例４９
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−グアニジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
３−ヒドロキシベンズアミジン 塩酸塩の合成
３−ヒドロキシベンゾニトリル５ｇ（４２ｍｍｏｌ）を塩化水素を３０％含有する（ｗ／ｖ）エタノール５０ｍｌに溶解し、室温で一晩撹拌した。溶媒を留去し得られた残渣をアンモニアを３０％含有する（ｗ／ｖ）エタノール溶液５０ｍｌに溶解して室温で一晩撹拌した後、溶媒を留去し表題化合物を得た。
収量 ４．４ｇ（２５．５ｍｍｏｌ） 収率 ６１％
工程２
Ｎ−ｔ−ブトキシカルボニル−３−ヒドロキシベンズアミジンの合成
３−ヒドロキシベンズアミジン 塩酸塩 １ｇ（５．８ｍｍｏｌ）、ジ−ｔ−ブチルジカルボネート１．２７ｇ（５．８ｍｍｏｌ）、４−（ジメチルアミノ）ピリジン２４ｍｇ（０．２ｍｍｏｌ）、トリエチルアミン１．３０ｇ（１２．８ｍｍｏｌ）をジメチルホルムアミド２０ｍｌに溶解し、室温で一晩撹拌した。反応液を水に開け酢酸エチルで抽出したのち、有機層を１規定水酸化ナトリウム水溶液で抽出した。水層を濃塩酸で弱アルカリ性とし、酢酸エチルを抽出溶媒として常法に従って処理し表題化合物を得た。
収量 ４５８ｍｇ（１．９４ｍｍｏｌ） 収率 ３３％
H-NMR(DMSO-d6)δ1.45(9H,s),6.95(1H,d),7.25(1H,t),7.35(1H,d),7.38(1H,s),8.90(2H,br),9.65(1H,br)
工程３
３−（２−アミノエトキシ）ベンズアミジン 二塩酸塩の合成
Ｎ−ｔ−ブトキシカルボニル−３−ヒドロキシベンズアミジン、ｔ−ブチル−Ｎ−（２−ブロモエチル）カルバマートを出発原料とし実施例１工程２と同様の操作によりＮ−ｔ−ブトキシカルボニル−３−［２−（ｔ−ブトキシカルボニルアミノ）エトキシ］ベンズアミジンを得た。これを精製せずに実施例１工程３と同様にして表題化合物を得た。
H-NMR(DMSO-d6)δ3.20(2H,t),4.35(2H,t),7.34(1H,d),7.44-7.60(3H,m),8.36(3H,br),9.28(2H,br),9.50(2H,br)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−グアニジノベンズアミド 二トリフルオロ酢酸塩の合成
４−グアニジノ安息香酸 塩酸塩１５２ｍｇ（０．７ｍｍｏｌ）、３−（２−アミノエトキシ）ベンズアミジン 二塩酸塩１６６ｍｇ（０．６６ｍｍｏｌ）、トリエチルアミン１４２ｍｇ（１．４ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）１１０ｍｇ（０．７ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１３４ｍｇ（０．７ｍｍｏｌ）をジメチルホルムアミド３ｍｌ中、室温下一晩撹拌した。溶媒を減圧留去後、残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １７２ｍｇ（０．３ｍｍｏｌ） 収率 ４６％
MS(ESI,m/z)341(MH+)
H-NMR(DMSO-d6)δ3.65(2H,dt),4.20(2H,t),7.28-7.42(5H,m),7.53(1H,t),7.70(4H,brs),7.93(2H,d),8.78(1H,t),9.20(2H,br),9.30(2H,br),10.15(1H,s)
実施例５０
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１−フェノキシカルボニル−４−ピペリジルオキシ）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンズアミドを４規定塩化水素を含むジオキサンおよびエタノールを用いて反応させて得た３−［２−［４−（４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］ベンズイミド酸エチル 二塩酸塩９６．４ｍｇ（０．２２１ｍｍｏｌ）と、クロロギ酸フェニル７０．０ｍｇ（０．４４７ｍｍｏｌ）、ジイソプロピルエチルアミン７４２ｍｇ（６．０７ｍｍｏｌ）をジクロロメタン１５ｍｌ中で反応させた後、１０％アンモニアを含む（ｗ／ｖ）エタノールを用いて常法に従いアミジン化を行い、オクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ５４．５ｍｇ（０．０８８５ｍｍｏｌ） 収率 ４０．０％
MS(ESI,m/z)503(MH+)
H-NMR(DMSO-d6)δ1.60-2.07(4H,m),3.23-4.85(6H,m),4.10-4.21(2H,m),4.63-4.80(1H,m),7.03-7.58(11H,m),7.82(2H,d),8.55(1H,t),9.05(2H,brs),9.23(2H,brs)
実施例５１
（３Ｓ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸 二トリフルオロ酢酸塩および
（３Ｓ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸エチル 二トリフルオロ酢酸塩の合成
工程１
（３Ｓ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｌ−アスパラギン酸−β−ベンジルエステル９７０ｍｇ（３．０ｍｍｏｌ）、トリエチルアミン０．４２ｍｌ（３．０ｍｍｏｌ）をテトラヒドロフラン１５ｍｌに溶解し、氷冷下クロロギ酸エチル０．２９ｍｌ（３．０ｍｍｏｌ）を加え２０分間撹拌した。生じた析出物を吸引濾過により除去し、濾液に氷３ｇ、水素化ホウ素ナトリウム２２７ｍｇ（６．０ｍｍｏｌ）を氷冷下加え１．５時間撹拌した。ここに１規定塩化水素水溶液を１０ｍｌを加え室温で更に１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた油状残渣をテトラヒドロフラン１２ｍｌに溶解し、３−シアノフェノール２８８ｍｇ（２．４１ｍｍｏｌ）、トリフェニルホスフィン６９０ｍｇ（２．６３ｍｍｏｌ）、アゾジカルボン酸ジエチル（４０％トルエン溶液）１．０５ｇ（２．４１ｍｍｏｌ）を加え室温で一晩撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ４５５ｍｇ（１．１１ｍｍｏｌ） 収率 ３７％
H-NMR(CDCl3)δ1.46(9H,s),2.79(2H,d),4.00(1H,dd),4.06(1H,dd),4.41(1H,br),5.13(2H,s),5.56(1H,br),7.05-7.18(4H,m),7.21-7.38(5H,m)
工程２
（３Ｓ）−３−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブチル酸ベンジルの合成
（３Ｓ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル４５５ｍｇ（１．１ｍｍｏｌ）を４規定塩化水素のジオキサン溶液５ｍｌに溶解し、０℃で６時間撹拌した。溶媒を留去し得られた油状残渣をジクロロメタン５ｍｌに溶解し、氷冷下４−シアノ安息香酸クロリド２７６ｍｇ（１．６７ｍｍｏｌ）、トリエチルアミン０．３１ｍｌ（２．２２ｍｍｏｌ）を加え、室温で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従らて処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２６０ｍｇ（０．５９ｍｍｏｌ） 収率 ５３％
H-NMR(CDCl3)δ2.86(1H,dd),2.95(1H,dd),4.12(1H,dd),4.20(1H,dd),4.85(1H,br),5.16(2H,s),7.09(1H,d),7.11(1H,dd),7.24-7.40(7H,m),7.72(2H,d),7.83(2H,d)
工程３
（３Ｓ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸エチル 二トリフルオロ酢酸塩の合成
（３Ｓ）−３−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブチル酸ベンジル２６０ｍｇ（０．５９ｍｍｏｌ）を塩化水素を３０％含有する（ｗ／ｖ）エタノール５ｍｌに加え、室温で一晩撹拌した。続いて溶媒を減圧下留去した後、室温でアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液５ｍｌに溶解して室温で二晩撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １１３ｍｇ（０．１７６ｍｍｏｌ） 収率 ３０％
MS(ESI,m/z)412(MH+)
H-NMR(DMSO-d6)δ1.15(3H,t),2.82(2H,d),4.07(2H,q),4.12(1H,dd),4.24(1H,dd),4.72(1H,br),7.33(1H,d),7.39(1H,s),7.40(1H,d),7.54(1H,dd),7.91(2H,d),8.02(2H,d),8.84(1H,d),9.16(2H,s),9.28(4H,s),9.42(2H,s)
工程４
（３Ｓ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸 二トリフルオロ酢酸塩の合成
（３Ｓ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸エチル 二トリフルオロ酢酸塩３３８ｍｇ（０．５２８ｍｍｏｌ）を濃塩酸１０ｍｌに溶解し４０℃で６時間撹拌した。溶媒を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ４１ｍｇ（０．０６７ｍｍｏｌ） 収率 １３％
MS(ESI,m/z)384(MH+)
H-NMR(DMSO-d6)δ2.74(2H,d),4.13(1H,dd),4.24(1H,dd),4.69(1H,ddt),7.35(1H,d),7.40(1H,d),7.41(1H,s),7.55(1H,dd),7.91(2H,d),8.03(2H,d),8.81(1H,d),9.20(2H,s),9.28(2H,s),9.33(2H,s),9.43(2H,s)
実施例５２
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（ピペリジン−４−イル）メチルベンゾイルアミノ］ブチル酸エチル 二トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−アスパラギン酸−β−ベンジルエステル３．２３ｇ（１０．０ｍｍｏｌ）、トリエチルアミン１．３９ｍｌ（１０．０ｍｍｏｌ）をテトラヒドロフラン５０ｍｌに溶解し、氷冷下クロロギ酸エチル０．９６ｍｌ（１０．０ｍｍｏｌ）を加え２０分間撹拌した。生じた析出物を吸引濾過により除去し、濾液に氷５ｇ、水素化ホウ素ナトリウム０．７６ｇ（２０．０ｍｍｏｌ）を氷冷下加え１．５時間撹拌した。ここに１規定塩化水素水溶液を２０ｍｌを加え室温で更に１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた油状残渣をテトラヒドロフラン３６ｍｌに溶解し、３−シアノフェノール０．９６ｇ（８．０４ｍｍｏｌ）、トリフェニルホスフィン２．３０ｇ（８．７７ｍｍｏｌ）、アゾジカルボン酸ジエチル（４０％トルエン溶液）３．５０ｇ（８．０４ｍｍｏｌ）を加え室温で一晩撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．８０ｇ（４．３８ｍｍｏｌ） 収率 ４４％
H-NMR(CDCl3)δ1.46(9H,s),2.79(2H,d),4.00(1H,dd),4.06(1H,dd),4.41(1H,br),5.13(2H,s),5.56(1H,br),7.05-7.18(4H,m),7.21-7.38(5H,m)
工程２
（３Ｒ）−３−アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジルエステル塩酸塩 （３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸ベンジルを原料とし、４規定塩化水素を含むジオキサンを用いて常法により脱ｔ−ブトキシカルボニル反応を行い表題化合物を得た。
工程３
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（ピペリジン−４−イル）メチルベンゾイルアミノ］ブチル酸エチル 二トリフルオロ酢酸塩の合成
４−［１−（ｔ−ブトキシカルボニル）ピペリジン−４−イリデン］メチル安息香酸メチル３３４ｍｇ（１．００ｍｍｏｌ）に、パラジウム−炭素９５ｍｇ、メタノール２０ｍｌを加え、水素存在下１５時間撹拌した。セライト濾過後、溶媒を留去して得られた残留物に１規定水酸化ナトリウム４ｍｌ、エタノール６ｍｌを加え、１８時間撹拌した。反応液を１規定塩酸で酸性にした後、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をジクロロメタン５ｍｌに溶解させ、トリエチルアミン０．４６ｍｌ（３．２７ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２０９ｍｇ（１．５０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１４７ｍｇ（１．０９ｍｍｏｌ）、（３Ｒ）−３−アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジルエステル塩酸塩３０６ｍｇ（０．９９ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １０５ｍｇ（０．２２ｍｍｏｌ） 収率 ２２％
MS(ESI,m/z)464(MH+)
H-NMR(DMSO-d6)δ1.15(3H,t),1.22-1.40(2H,m),1.62-1.74(2H,m),1.78-1.90(1H,m),2.56-2.65(2H,m),2.69-2.90(4H,m),3.16-3.31(2H,m),4.01-4.16(3H,m),4.18-4.27(1H,m),4.64-4.78(1H,m),7.27-7.45(6H,m),7.78(2H,d),8.28(1H,br),8.47-8.65(2H,m),9.16(4H,br),9.29(2H,br)
実施例５３
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（１−ピペリジン−４−イル）メチルベンゾイルアミノ］ブチル酸 二トリフルオロ酢酸塩の合成
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（１−ピペリジン−４−イル）メチルベンゾイルアミノ］ブチル酸エチル 二トリフルオロ酢酸塩３０ｍｇ（０．０５ｍｍｏｌ）を出発原料として、実施例５１工程４と同様の操作に従って表題化合物を得た。
収量 １７ｍｇ（０．２２ｍｍｏｌ） 収率 ６２％
MS(ESI,m/z)439(MH+)
H-NMR(DMSO-d6)δ1.26-1.45(2H,m),1.61-1.73(2H,m),1.74-1.89(1H,m),2.58(2H,d),2.67-2.85(4H,m),3.24-3.36(2H,m),4.10(1H,dd),4.24(1H,dd),4.68(1H,ddt),7.27(2H,d),7.33(1H,d),7.43(2H,br),8.28(1H,br),8.47-8.65(2H,m),9.16(4H,br),9.29(2H,br)
実施例５４
（３Ｒ）−３−［（ビフェニル−４−カルボニル）アミノ］−４−（３−アミジノフェノキシ）ブチル酸エチル トリフルオロ酢酸塩の合成
工程１
４−フェニルベンゾイルクロライドの合成
４−フェニル安息香酸１．０５ｇ（５．３ｍｍｏｌ）に塩化チオニル１０ｍｌを加え３時間加熱還流した。溶媒を留去し粗製物を得た。
工程２
（３Ｒ）−３−［（ビフェニル−４−カルボニル）アミノ］−４−（３−シアノフェノキシ）ブチル酸ベンジルの合成
（３Ｒ）−３−アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル塩酸塩３１０ｍｇ（１．０ｍｍｏｌ）をジメチルホルムアミド１０ｍｌに溶解させ、トリエチルアミン０．１８ｍｌ（１．３ｍｍｏｌ）を加えた。氷冷下、４−フェニルベンゾイルクロライド２８２ｍｇ（１．３ｍｍｏｌ）を加え３０分撹拌後、室温に戻して２時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定塩酸、飽和重曹水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ２２０ｍｇ（０．４５ｍｍｏｌ） 収率 ４５％
H-NMR(CDCl3)δ2.93(2H,dt),4.19(2H,dt),4.83-4.97(1H,m),7.14(2H,dd),7.24-7.29(2H,m),7.33-7.51(8H,m),7.59-7.68(4H,m),7.83(2H,d)
工程３
（３Ｒ）−３−［（ビフェニル−４−カルボニル）アミノ］−４−（３−アミジノフェノキシ）ブチル酸エチル トリフルオロ酢酸塩の合成
（３Ｒ）−［（ビフェニル−４−カルボニル）アミノ］−４−（３−シアノフェノキシ）ブチル酸ベンジル２２０ｍｇ（０．４５ｍｍｏｌ）を出発原料として、実施例１工程６と同様の操作に従って表題化合物を得た。
収量 １１５ｍｇ（０．２１ｍｍｏｌ） 収率 ４６％
MS(ESI,m/z)446(MH+)
H-NMR(DMSO-d6)δ1.16(3H,t),2.80(2H,d),4.07(2H,q),4.08-4.17(1H,m),4.20-4.29(1H,m),4.64-4.68(1H,m),7.29-7.59(7H,m),7.74(2H,d),7.78(2H,d),7.93(2H,d),8.62(1H,d),9.11(2H,br),9.29(2H,br)
実施例５５
（３Ｒ）−３−［（ビフェニル−４−カルボニル）アミノ］−４−（３−アミジノフェノキシ）ブチル酸 トリフルオロ酢酸塩の合成
（３Ｒ）−３−［（ビフェニル−４−カルボニル）アミノ］−４−（３−アミジノフェノキシ）ブチル酸エチル トリフルオロ酢酸塩１２０ｍｇ（０．１８ｍｍｏｌ）を濃塩酸５ｍｌ溶解させ６０℃で１９時間撹拌し、溶媒を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １４ｍｇ（０．０３ｍｍｏｌ） 収率 １５％
MS(ESI,m/z)418(MH+)
H-NMR(DMSO-d6)δ2.71(2H,d),4.09-4.20(1H,m),4.21-4.30(1H,m),4.63-4.75(1H,m),7.33-7.59(7H,m),7.74(2H,d),7.78(2H,d),7.95(2H,d),8.61(1H,d),9.22(4H,br)
実施例５６
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［（４−ジメチルカルバモイルベンゾイル）アミノ］ブチル酸 トリフルオロ酢酸塩の合成
工程１ ４−ジメチルカルバモイル安息香酸の合成
５０％ジメチルアミン水溶液３０ｍｌにテレフタル酸モノメチルエステル クロライド５ｇ（２５．２ｍｍｏｌ）をジオキサン２０ｍｌに溶かして氷冷下加えた。３０分撹拌後、１規定水酸化ナトリウム水溶液５０ｍｌを加え室温で２日間撹拌した。反応液を酢酸エチルで洗浄後、塩酸で酸性とし酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を留去して得られた残留物をヘキサンで洗浄、乾燥し表題化合物を得た。
収量 ２．５８ｇ（１３．４ｍｍｏｌ） 収率 ５３％
H-NMR(CDCl3)δ2.85(3H,br),2.95(3H,br),7.50(2H,d),7.97(2H,d)
工程２
（３Ｒ）−４−（３−シアノフェノキシ）−３−［（４−ジメチルカルバモイルベンゾイル）アミノ］ブチル酸ベンジルの合成
（３Ｒ）−４−（３−シアノフェノキシ）−３−アミノブチル酸ベンジル塩酸塩に１規定水酸化ナトリウム水溶液を加え酢酸エチルを抽出溶媒として常法により処理して得られた（３Ｒ）−４−（３−シアノフェノキシ）−３−アミノブチル酸ベンジル３００ｍｇ（０．９７ｍｍｏｌ）と４−ジメチルカルバモイル安息香酸１９３ｍｇ（１ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１９２ｍｇ（１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１５５ｍｇ（１ｍｍｏｌ）をジクロロメタン１０ｍｌ中室温で一晩撹拌した。反応液へ１規定塩酸を加え、ジクロロメタンで抽出。有機層を１規定水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １７８ｍｇ（０．３７ｍｍｏｌ） 収率 ３７％
H-NMR(DMSO-d6)δ2.82(2H,d),2.90(3H,br),3.00(3H,br),4.05-4.25(2H,m),4.70(1H,m),5.10(2H,s),7.26-7.35(6H,m),7.38-7.51(5H,m),7.84(2H,d),8.64(1H,d)
工程３
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［（４−ジメチルカルバモイルベンゾイル）アミノ］ブチル酸 トリフルオロ酢酸塩の合成
（３Ｒ）−４−（３−シアノフェノキシ）−３−［（４−ジメチルカルバモイルベンゾイル）アミノ］ブチル酸ベンジル１７８ｍｇ（０．３８ｍｍｏｌ）を４規定塩化水素を含むジオキサン６ｍｌ中で撹拌し、エタノール１ｍｌを加えて室温で６日間撹拌後溶媒を減圧留去した。得た残渣をエタノール１０ｍｌ中撹拌し、アンモニウムカルボナート６０ｍｇを加え２日間室温で撹拌し、溶媒を留去した。得られた残留物へ濃塩酸１５ｍｌを加え、４０℃で一晩撹拌後、溶媒を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １０８ｍｇ（０．２１ｍｍｏｌ） 収率 ５５％
MS(ESI,m/z)413(MH+)
H-NMR(DMSO-d6)δ2.80(2H,d),3.00(3H,br),3.10(3H,br),4.15-4.35(2H,m),4.75(1H,m),7.40-7.49(3H,m),7.54-7.64(3H,m),7.96(2H,d),8.70(1H,d),9.15(2H,br),9.35(2H,br)
実施例５７
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［（４−グアニジノベンゾイル）アミノ］ブチル酸 二トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−４−（３−シアノフェノキシ）−３−［（４−グアニジノベンゾイル）アミノ］ブチル酸ベンジル トリフルオロ酢酸塩の合成
（３Ｒ）−４−（３−シアノフェノキシ）−３−アミノブチル酸ベンジル２４７ｍｇ（０．８ｍｍｏｌ）、４−グアニジノ安息香酸 一塩酸塩１３８ｍｇ（０．６４ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）１００ｍｇ（０．６４ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１２３ｍｇ（０．６４ｍｍｏｌ）をジメチルホルムアミド５ｍｌ中室温で３日撹拌後、溶媒を減圧留去し１規定水酸化ナトリウム水溶液を加え、ジクロロメタンで抽出。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １２３ｍｇ（０．２１ｍｍｏｌ） 収率 ３３％
H-NMR(CD3OD)δ2.90(2H,m),4.20(2H,m),4.85(1H,m),5.15(2H,s),7.20-7.38(10H,m),7.41(1H,t),7.82(2H,d)
工程２
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［（４−グアニジノベンゾイル）アミノ］ブチル酸 二トリフルオロ酢酸塩の合成
（３Ｒ）−４−（３−シアノフェノキシ）−３−［（４−グアニジノベンゾイル）アミノ］ブチル酸ベンジル トリフルオロ酢酸塩１７８ｍｇ（０．３ｍｍｏｌ）を用いて実施例５６工程３と同様にして表題化合物を得た。
収量 １１１ｍｇ（０．１８ｍｍｏｌ） 収率 ６０％
MS(ESI,m/z)399(MH+)
H-NMR(DMSO-d6)δ2.75(2H,d),4.05-4.25(2H,m),4.70(1H,m),7.30-7.43(5H,m),7.53(1H,t),7.68(4H,s),7.92(2H,d),8.58(1H,d),9.13(2H,s),9.30(2H,s),10.13(1H,s)
実施例５８
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（ピロリジン−１−イル）ベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩の合成
（３Ｒ）−３−（ｔ−ブトキシカルボニル）アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル５０５ｍｇ（１．２３ｍｍｏｌ）を４規定塩酸ジオキサン５ｍｌ、ジオキサン２．５ｍｌに溶解させ、１５時間撹拌した。溶媒留去後、残留物をジクロロメタン１０ｍｌに溶解させ、４−（ピロリジン−１−イル）安息香酸３３４ｍｇ（１．００ｍｍｏｌ）トリエチルアミン０．８６ｍｌ（６．１５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２５８ｍｇ（１．３５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１８３ｍｇ（１．３５ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を４規定塩酸ジオキサン５ｍｌ、エタノール１ｍｌを加え９６時間撹拌した。溶媒を減圧留去して得られた残留物をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１０ｍｌに溶解して２４時間撹拌した。溶媒を減圧留去して得られた残留物に濃塩酸５ｍｌを加え５０℃で１５時間撹拌した。溶媒を減圧留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １７０ｍｇ（０．３２ｍｍｏｌ） 収率 ２４％
MS(ESI,m/z)411(MH+)
H-NMR(DMSO-d6)δ1.87-2.03(4H,m),2.70(2H,d),3.20-3.35(4H,m),4.04(1H,dd),4.21(1H,dd),4.63(1H,ddt),6.53(2H,d),7.32-7.45(3H,m),7.53(1H,dd),7.72(2H,d),8.11(1H,d),9.06(2H,br),9.27(2H,br)
実施例５９
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（ピロリジン−１−イル）ベンゾイルアミノ］ブチル酸エチル トリフルオロ酢酸塩の合成
（３Ｒ）−４−（３−シアノフェノキシ）−３−［４−（ピロリジン−１−イル）ベンゾイルアミノ］ブチル酸ベンジルの合成
（３Ｒ）−３−（ｔ−ブトキシカルボニル）アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル５．１ｇ（１２．４ｍｍｏｌ）を４規定塩酸ジオキサン２０ｍｌ、ジオキサン１０ｍｌに溶解させ、１５時間撹拌した。溶媒留去後、残留物をジクロロメタン１０ｍｌに溶解させ、４−（ピロリジン−１−イル）安息香酸２．６１ｇ（１３．７ｍｍｏｌ）、トリエチルアミン８．６３ｍｌ（６２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２．６１ｇ（１３．７ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１．８５ｍｇ（１３．７ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例１工程６と同様の操作に従って表題化合物を得た。
収量 ８００ｍｇ（１．４５ｍｍｏｌ） 収率 ２８％
MS(ESI,m/z)439(MH+)
H-NMR(DMSO-d6)δ1.14(3H,t),1.86-2.01(4H,m),2.70(2H,d),3.18-3.33(4H,m),4.02(1H,dd),4.10(1H,q),4.21(1H,dd),4.63(1H,ddt),6.53(2H,d),7.35-7.51(3H,m),7.53(1H,dd),7.72(2H,d),8.11(1H,d),9.04(2H,br),9.28(2H,br)
実施例６０
（３Ｒ）−３−（４−カルバモイルベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸 二トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−３−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブチル酸ベンジルの合成
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル１．８ｇ（４．３８ｍｍｏｌ）を４規定塩化水素のジオキサン溶液２０ｍｌに溶解し、０℃で６時間撹拌した。溶媒を留去し得られた油状残渣をジクロロメタン５ｍｌに溶解し、氷冷下４−シアノ安息香酸クロリド１．０９ｇ（６．５８ｍｍｏｌ）、トリエチルアミン１．２２ｍｌ（８．７６ｍｍｏｌ）を加え、室温で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 １．２１ｇ（２．７５ｍｍｏｌ） 収率 ６３％
H-NMR(CDCl3)δ2.86(1H,dd),2.95(1H,dd),4.12(1H,dd),4.20(1H,dd),4.85(1H,br),5.16(2H,s),7.09(1H,d),7.11(1H,dd),7.24-7.40(7H,m),7.72(2H,d),7.83(2H,d)
工程２
（３Ｒ）−３−（４−カルバモイルベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸 二トリフルオロ酢酸塩の合成
（３Ｒ）−３−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブチル酸ベンジルを塩化水素を３０％含有する（ｗ／ｖ）エタノールに加え、室温で一晩撹拌した。続いて室温でアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液に溶解して室温で二晩撹拌した。溶媒を留去して得られた残留物を濃塩酸に溶解し４０℃で６時間撹拌した。塩化水素を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
MS(ESI,m/z)385(MH+)
H-NMR(DMSO-d6)δ2.75(2H,d),4.12(1H,dd),4.23(1H,dd),4.68(1H,br),7.35(1H,d),7.40(1H,d),7.42(1H,s),7.53(1H,t),7.89(2H,d),7.96(2H,d),8.09(2H,br),8.66(1H,d),9.24(2H,br),9.29(2H,br)
実施例６１
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［（４−ジメチルアミノ）ベンゾイルアミノ］ブチル酸エチル トリフルオロ酢酸塩および
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［（４−ジメチルアミノ）ベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩の合成
（３Ｒ）−３−（ｔ−ブトキシカルボニル）アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル７００ｍｇ（１．７０ｍｍｏｌ）を４規定塩酸ジオキサン５ｍｌ、ジオキサン２．５ｍｌに溶解させ、１５時間撹拌した。溶媒留去後、残留物をジクロロメタン１０ｍｌに溶解させ、４−ジメチルアミノ安息香酸２８２ｍｇ（１．７１ｍｍｏｌ）、トリエチルアミン１．１９ｍｌ（８．５５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩７４８ｍｇ（１．８８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２５４ｍｇ（１．８８ｍｍｏｌ）を加え１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物を実施例５６工程３と同様の操作に従って表題化合物を得た。ただしエタノール中アンモニウムカルボナートの代わりに１０％アンモニアを含むエタノールを用いた。
（３Ｒ）−４−（３−アミジノフェノキシ）−３−（４−ジメチルアミノベンゾイルアミノ］ブチル酸エチル トリフルオロ酢酸塩
収量 １０ｍｇ（０．０２ｍｍｏｌ） 収率 １％
MS(ESI,m/z)413(MH+)
H-NMR(DMSO-d6)δ1.14(3H,t),2.78(2H,d),2.97(6H,s),4.06(2H,q),4.10(2H,dd),4.23(2H,dd),4.68(2H,dd),6.69(2H,d),7.30-7.42(3H,m),7.53(1H,dd),7.71(2H,d),8.18(2H,d),9.10(2H,br),9.28(2H,br)
（３Ｒ）−４−（３−アミジノフェノキシ）−３−（４−ジメチルアミノベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩
収量 ７０ｍｇ（０．１４ｍｍｏｌ） 収率 ８％
MS(ESI,m/z)385(MH+)
H-NMR(DMSO-d6)δ2.69(2H,d),2.97(6H,s),4.04(2H,dd),4.22(2H,dd),4.64(2H,q),6.70(2H,d),7.33-7.44(3H,m),7.53(1H,dd),7.72(2H,d),8.14(2H,d),9.09(2H,br),9.25(2H,br)
実施例６２
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）ベンゾイルアミノ］ブチル酸 二トリフルオロ酢酸塩の合成
工程１
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸エチルの合成
４−ヒドロキシピペリジンをジ−ｔ−ブチルジカルボネートを用いて常法によりｔ−ブトキシカルボニル化して得た１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン１．７６ｇ（９．３ｍｍｏｌ）と、４−ヒドロキシ安息香酸エチル１．７ｇ（１０．２ｍｍｏｌ）、トリフェニルホスフィン２．４４ｇ（９．３ｍｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解し、アゾジカルボン酸ジエチル１．６２ｇ（９．３ｍｍｏｌ）を室温で加え一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．５７ｇ（４．５ｍｍｏｌ） 収率 ４４％
H-NMR(CDCl3)δ1.38(3H,t),1.50(9H,s)1.70-1.80(2H,m),1.90-2.00(2H,m),3.30-3.41(2H,m),3.63-3.75(2H,m),4.35(2H,q),4.55(1H,m),6.90(2H,d),8.00(2H,d)
工程２
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸の合成
（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸エチル８４７ｍｇ（２．４３ｍｍｏｌ）をエタノール５０ｍｌに溶解し、１規定水酸化ナトリウム溶液を５ｍｌを加え３日間室温で撹拌した。反応液を濃縮し、酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ６９７ｍｇ（２．２ｍｍｏｌ） 収率 ９２％
H-NMR(CDCl3)δ1.50(9H,s),1.70-2.00(4H,m),3.30-3.40(2H,m),3.65-3.75(2H,m),4.60(1H,s),6.95(2H,d),8.05(2H,d)
工程３
（３Ｒ）−４−（３−シアノフェノキシ）−３−［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンゾイルアミノ］ブチル酸ベンジルの合成
（３Ｒ）−３−（ｔ−ブトキシカルボニル）アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル１．４６ｇ（３．５６ｍｍｏｌ）を４規定塩酸ジオキサン１０ｍｌ、ジオキサン５ｍｌに溶解させ、１５時間撹拌した。溶媒留去後、残留物をジクロロメタン２０ｍｌに溶解させ、、４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸１．１４ｇ（３．５６ｍｍｏｌ）トリエチルアミン２．４８ｍｌ（１７．８ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩７４８ｍｇ（３．９２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール５２９ｍｇ（３．９２ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 １．０ｇ（１．６３ｍｍｏｌ） 収率 ４６％
H-NMR(CDCl3)δ1.45(9H,s),1.68-1.81(2H,m),1.84-1.97(2H,m),2.88(2H,dt),3.27-3.40(2H,m),3.61-3.73(2H,m),4.04-4.23(2H,m),4.46-4.58(1H,m),4.77-4.90(1H,m),5.13(2H,s),6.89(2H,d),7.02-7.13(3H,m),.7.27-7.37(6H,m),7.68(2H,d)
工程４
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）ベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩の合成
（３Ｒ）−４−（３−シアノフェノキシ）−３−［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンゾイルアミノ］ブチル酸ベンジル１．０ｇ（１．６３ｍｍｏｌ）に４規定塩酸ジオキサン１０ｍｌ、エタノール２ｍｌを加え４８時間撹拌した。溶媒を留去後、アンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１０ｍｌに溶解して２４時間撹拌した。溶媒を留去後、エタノール１０ｍｌに溶解させ、エチルアセトイミダート塩酸塩１．０ｇ（８．１６ｍｍｏｌ）、トリエチルアミン１．１ｍｌ（８．１６ｍｍｏｌ）を加え、２４時間撹拌した。溶媒を留去後、濃塩酸１０ｍｌに溶解させ、４０℃で１８時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ６００ｍｇ（０．８５ｍｍｏｌ） 収率 ５２％
MS(ESI,m/z)482(MH+)
H-NMR(DMSO-d6)δ1.66-1.85(2H,m),2.02-2.16(2H,m),2.29(3H,s),2.71(2H,d),3.43-3.56(3H,m),4.00-4.13(2H,m),4.18-4.30(2H,m),4.58-4.63(2H,m),4.76-4.86(1H,m),7.07(2H,d),7.32-7.50(3H,m),7.54(1H,dd),7.84(2H,d),8.39(1H,d),8.60(1H,br),9.09(2H,br),9.14(1H,br),9.28(2H,br)
実施例６３
３−［５−（４−アミジノフェニル）−５−オキソペンチル］オキシベンズアミジン 二トリフルオロ酢酸塩の合成
工程１
４−（５−クロロ−１−オキソペンチル）ベンゾニトリルの合成
４−アセチルベンゾニトリル１ｇ（６．９ｍｍｏｌ）をテトラヒドロフラン８ｍｌに溶解し、リチウムビストリメチルシリルアミド（１Ｍヘキサン溶液）９ｍｌを−７０℃で徐々に加え３０分撹拌した。テトラヒドロフラン６ｍｌに溶解した１−クロロ−３−ヨードプロパン１．４３ｇ（７ｍｍｏｌ）を加え室温で一晩撹拌した。反応液を水に注ぎ、酢酸エチルで抽出し、１規定塩酸、飽和食塩水で洗浄後、粉末硫酸マグネシウムで乾燥し、溶媒を留去した。残留物をシリカゲルクロマトグラフィーで精製することにより表題化合物を得た。
収量 ５９．３ｍｇ（０．２７ｍｍｏｌ） 収率 ３．９％
H-NMR(CDCl3)δ1.82-1.95(4H,m),3.03(2H,t),3.60(2H,t),7.80(2H,d),8.05(2H,d)
工程２
３−［５−（４−シアノフェニル）−５−オキソペンチル］オキシベンゾニトリルの合成 ４−（５−クロロ−１−オキソペンチル）ベンゾニトリル５３ｍｇ（０．２４ｍｍｏｌ）、をジメチルホルムアミド２ｍｌに溶解し、炭酸カリウム３３ｍｇ（０．２４ｍｍｏｌ）、ヨウ化カリウム４０ｍｇ、３−ヒドロキシベンゾニトリル２９ｍｇ（０．２４ｍｍｏｌ）を加え７０℃で一晩撹拌した。１規定塩酸を加え、酢酸エチルで抽出後、１規定水酸化ナトリウム、飽和食塩水で洗浄し、粉末硫酸マグネシウムで乾燥、溶媒を留去した。シリカゲルクロマトグラフィーに付し表題化合物を得た。
収量 ２４ｍｇ（０．０７９ｍｍｏｌ） 収率 ３３％
H-NMR(CDCl3)δ1.82-2.00(4H,m),3.08(2H,t),4.02(2H,t),7.12(1H,d),7.14(1H,s),7.22(1H,d),7.37(1H,t),7.79(2H,d),8.03(2H,d)
工程３
３−［５−（４−アミジノフェニル）−５−オキソペンチル］オキシベンズアミジン 二トリフルオロ酢酸塩の合成
３−［５−（４−シアノフェニル）−５−オキソペンチル］オキシベンゾニトリル４３ｍｇ（０．１４ｍｍｏｌ）を出発原料とし実施例１工程６と同様の操作により表題化合物を得た。収量 ８．８ｍｇ（０．０１５ｍｍｏｌ） 収率 １１％
MS(ESI,m/z)339(MH+)
H-NMR(DMSO-d6)δ1.78-1.90(4H,m),3.20(2H,t),4.12(2H,t),7.30(1H,d),7.37(1H,s),7.39(1H,d),7.53(1H,t),7.94(2H,d),8.16(2H,d),9.24-9.48(8H,brm)
実施例６４
４−［４−（３−アミジノフェノキシ）ブチリル］−Ｎ、Ｎ−ジメチルベンズアミド トリフルオロ酢酸塩の合成
工程１
２−（４−ブロモフェニル）−２−（３−クロロプロピル）−５、５−ジメチル−１、３−ジオキサンの合成
４’−ブロモ−４−クロロブチロフェノン１０ｇ（３８．２ｍｍｏｌ）、２、２−ジメチル−１、３−プロパンジオール４ｇ（３８．２ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物２００ｍｇ（１ｍｍｏｌ）をベンゼン中三日間加熱環流し共沸的に脱水を行った。飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物を得た。
収量 １３．３ｇ（３８ｍｍｏｌ） 収率 １００％
H-NMR(CDCl3)δ0.60(3H,s),1.22(3H,s),1.78-2.00(4H,m),3.40(4H,s),3.50(1H,t),7.25(2H,d),7.55(2H,d)
工程２
３−［３−［２−（４−ブロモフェニル）−５、５−ジメチル−１、３−ジオキサン−２−イル］プロポキシ］ベンゾニトリルの合成
水素化ナトリウム（油性、６０％）２３６ｍｇ（５．９ｍｍｏｌ）をジメチルホルムアミド中撹拌し、氷冷下３−ヒドロキシベンゾニトリル６９１ｍｇ（５．８ｍｍｏｌ）を加えた。室温で３０分撹拌した後２−（４−ブロモフェニル）−２−（３−クロロプロピル）−５、５−ジメチル−１、３−ジオキサン２ｇ（５．７５ｍｍｏｌ）をジメチルホルムアミドに溶解して加え、１００℃で一晩撹拌した。水を加え酢酸エチルで抽出し、有機層を１規定水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物の粗精製物を得た。収量 ２．２５ｇ（５．２３ｍｍｏｌ） 収率 ９１％
H-NMR(CDCl3)δ0.60(3H,s),1.22(3H,s),1.80-2.00(4H,m),3.40(4H,s),3.93(1H,s),7.06(1H,d),7.08(1H,s),7.19(1H,d),7.26-7.35(3H,m),7.52(2H,d)
工程３
４−［４−（３−シアノフェノキシ）ブチリル］安息香酸の合成
３−［３−［２−（４−ブロモフェニル）−５、５−ジメチル−１、３−ジオキサン−２−イル］プロポキシ］ベンゾニトリル５００ｍｇ（１．１６ｍｍｏｌ）、トリブチルアミン２６０ｍｇ（１．４ｍｍｏｌ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）クロライド４２ｍｇ（０．０６ｍｍｏｌ）を１−ブタノール３ｍｌ、ジメチルホルムアミド５ｍｌ中一酸化炭素雰囲気下１００℃で一晩撹拌した。反応液にエーテルを加え水で洗浄し、０．５Ｎ塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去した。残留物に６規定塩酸９ｍｌ、酢酸９ｍｌを加えて４時間加熱環流した。溶媒を留去し、飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで洗浄した。水層に塩酸を加え酸性とし、酢酸エチルで抽出し有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物粗製物を得た。収量 ２４７ｍｇ（０．８０ｍｍｏｌ） 収率 ６９％
H-NMR(DMSO-d6)δ2.10(2H,m),3.25(2H,t),4.10(2H,t),7.28(1H,d),7.36-7.52(3H,m),8.07(4H,s)
工程４
４−［４−（３−シアノフェノキシ）ブチリル］−Ｎ、Ｎ−ジメチルベンズアミドの合成 ４−［４−（３−シアノフェノキシ）ブチリル］安息香酸２４０ｍｇ（０．７８ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１５０ｍｇ（０．７８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水、８７％）１２１ｍｇ（０．７８ｍｍｏｌ）、５０％ジメチルアミン水溶液１００ｍｇをジメチルホルムアミド５ｍｌ中で室温下一晩撹拌した。１規定塩酸を加えジクロロメタンで抽出し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去した。残留物を酢酸エチルを溶出溶媒とするシリカゲルクロマトグラフィーで精製し、表題化合物を得た。
収量 １４９ｍｇ（０．４４ｍｍｏｌ） 収率 ５７％
H-NMR(CDCl3)δ2.25(2H,m),2.98(3H,s),3.18(3H,s),3.20(2H,t),4.10(2H,t),7.12(1H,d),7.14(1H,s),7.23(1H,d),7.36(1H,t),7.51(2H,d),8.02(2H,d)
工程５
４−［４−（３−アミジノフェノキシ）ブチリル］−Ｎ、Ｎ−ジメチルベンズアミド トリフルオロ酢酸塩の合成
４−［４−（３−シアノフェノキシ）ブチリル］−Ｎ、Ｎ−ジメチルベンズアミド７０ｍｇ（０．２１ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ４２ｍｇ（０．０９ｍｍｏｌ） 収率 ４３％
MS(ESI,m/z)354(MH+)
H-NMR(DMSO-d6)δ2.15(2H,m),2.83(3H,s),3.00(3H,s),3.25(2H,t),4.17(2H,t),7.30(1H,d),7.38(1H,s),7.40(1H,d),7.50-7.58(3H,m),8.04(2H,d),9.30(2H,br),9.40(2H,br)
実施例６５
４−［４−（３−アミジノフェノキシ）ブチリル］−Ｎ、Ｎ−ジメチルベンズアミジン 二トリフルオロ酢酸塩の合成
４−［４−（３−シアノフェノキシ）ブチリル］−Ｎ、Ｎ−ジメチルベンズアミド７０ｍｇ（０．２１ｍｍｏｌ）をジクロロメタン中撹拌しそこへトリメチルオキソニウム テトラフルオロボラート６７ｍｇ（０．４５ｍｍｏｌ）を加え室温で２日間撹拌した。エタノールを加えジクロロメタンを留去した後、アンモニウムカルボナート７１ｍｇを加えて室温で４日間撹拌した。溶媒を留去し、ジクロロメタンを加えて１規定塩酸で抽出した。水層に１規定水酸化ナトリウム水溶液を加えてアルカリ性としジクロロメタンで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥して溶媒を留去した。残留物を用いて実施例３工程３と同様にして表題化合物を得た。収量 ８ｍｇ（０．０１４ｍｍｏｌ） 収率 ７％
MS(ESI,m/z)353(MH+)
H-NMR(DMSO-d6)δ2.15(2H,m),3.00(3H,s),3.22(3H,s),3.30(2H,t),4.20(2H,t),7.29(1H,d),7.37(1H,s),7.38(1H,d),7.54(1H,t),7.76(2H,d),8.18(2H,d),9.03-9.42(6H,m)
実施例６６
４−［４−（３−アミジノフェノキシ）ブチリル］ベンズアミジン 二トリフルオロ酢酸塩の合成
工程１
４−［４−（３−シアノフェノキシ）ブチリル］ベンゾニトリルの合成
３−［３−［２−（４−ブロモフェニル）−５、５−ジメチル−１、３−ジオキサン−２−イル］プロポキシ］ベンゾニトリル５００ｍｇ（１．１６ｍｍｏｌ）、シアン化銅（Ｉ）１１４ｍｇ（１．２７ｍｍｏｌ）をジメチルホルムアミド１ｍｌ中で１４０℃で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去した。残留物にエタノール１０ｍｌ、６規定塩酸２ｍｌを加え５時間加熱環流した。溶媒を留去し、１規定塩酸を加え酢酸エチルで抽出、飽和食塩水で洗浄後無水硫酸マグネシウムで乾燥して溶媒を留去した。残留物を酢酸エチル−ヘキサンを溶出溶媒とするシリカゲルクロマトグラフィーで精製し表題化合物を得た。
収量 ５０ｍｇ（０．１７ｍｍｏｌ） 収率 １５％
H-NMR(CDCl3)δ2.28(2H,m),3.20(2H,t),4.10(2H,t),7.12(1H,d),7.13(1H,s),7.24(1H,d),7.36(1H,t),7.78(2H,d),8.07(2H,d)
工程２
４−［４−（３−アミジノフェノキシ）ブチリル］ベンズアミジン 二トリフルオロ酢酸塩の合成 ４−［４−（３−シアノフェノキシ）ブチリル］ベンゾニトリル５０ｍｇ（０．１７ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ３５ｍｇ（０．０６ｍｍｏｌ） 収率 ３５％
MS(ESI,m/z)353(MH+)
H-NMR(DMSO-d6)δ2.15(2H,m),3.30(2H,t),4.20(2H,t),7.30(1H,d),7.37(1H,s),7.38(1H,d),7.54(1H,t),7.95(2H,d),8.17(2H,d),9.18-9.50(8H,m)
実施例６７
４−（３−アミジノフェノキシ）−Ｎ−（４−アミジノフェニル）ブチルアミド 二トリフルオロ酢酸塩の合成
工程１
４−（３−シアノフェノキシ）−２−ブテン酸 エチルエステルの合成
エチル ４−ブロモクロトナート（７５％）１ｇ（３．９ｍｍｏｌ）、３−ヒドロキシベンゾニトリル４６５ｍｇ（３．９ｍｍｏｌ）、炭酸カリウム５３９ｍｇ（３．９ｍｍｏｌ）、ヨウ化カリウム６４７ｍｇ（３．９ｍｍｏｌ）をN,N−ジメチルホルムアミド中室温で三日間撹拌した。反応液に１規定塩酸を加え酢酸エチルで抽出、１規定水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物を得た。
収量 ８３２ｍｇ（３．６ｍｍｏｌ） 収率 ９３％
H-NMR(CDCl3)δ1.30(3H,t),4.20(2H,q),4.75(2H,m),6.17(1H,dt),7.05(1H,dt),7.12-7.18(2H,m),7.28(1H,d),7.40(1H,t)
工程２
４−（３−シアノフェノキシ）ブチル酸の合成
４−（３−シアノフェノキシ）−２−ブテン酸 エチルエステル８３０ｍｇ（３．６ｍｍｏｌ）、１規定水酸化ナトリウム水溶液１０ｍｌをエタノール５０ｍｌ中で６時間撹拌した。反応液を濃縮し、１規定塩酸を加えて生じた沈殿を濾取した。この濾取物にエタノール２０ｍｌ、１０％パラジウム炭素３０ｍｇを加え水素雰囲気下室温で１．５時間撹拌した。反応液を濾過し濾液を濃縮して得られた残留物に１規定塩酸を加え酢酸エチルで抽出、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物を得た。
収量 ２９０ｍｇ（１．４ｍｍｏｌ） 収率 ３９％
H-NMR(CDCl3)δ2.15(2H,m),2.60(2H,t),4.03(2H,t),7.09-7.14(2H,m),7.24(2H,d),7.36(1H,t)
工程３
４−（３−シアノフェノキシ）−Ｎ−（４−シアノフェニル）ブチルアミドの合成
４−（３−シアノフェノキシ）ブチル酸１００ｍｇ（０．４９ｍｍｏｌ）、トリエチルアミン５０ｍｇ（０．４９ｍｍｏｌ）をジメチルホルムアミド中氷冷下撹拌し、そこへクロロ蟻酸エチル５３ｍｇ（０．４９ｍｍｏｌ）を加えた。２分間撹拌後、ｐ−アミノベンゾニトリル５８ｍｇ（０．４９ｍｍｏｌ）を加えた後室温に昇温し一晩撹拌した。１規定塩酸を加え酢酸エチルで抽出し、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物の粗製物を得た。
収量 １１３ｍｇ（０．３７ｍｍｏｌ） 収率 ７６％
H-NMR(CDCl3)δ2.20(2H,m),2.60(2H,t),4.05(2H,t),7.08-7.14(2H,m),7.24(2H,d),7.36(2H,t),7.49(1H,br),7.58-7.68(4H,m)
工程４
４−（３−アミジノフェノキシ）−Ｎ−（４−アミジノフェニル）ブチルアミド 二トリフルオロ酢酸塩の合成
４−（３−シアノフェノキシ）−Ｎ−（４−シアノフェニル）ブチルアミド１１０ｍｇ（０．３６ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ５．２ｍｇ（０．００９ｍｍｏｌ） 収率 ３％
MS(ESI,m/z)340(MH+)
H-NMR(DMSO-d6)δ2.10(2H,m),2.60(2H,t),4.15(2H,t),7.30(1H,d),7.37(1H,s),7.39(1H,d),7.53(1H,t),7.80(4H,s),9.00-9.30(8H,m),10.45(1H,s)
実施例６８
３−（３−アミジノフェノキシ）−Ｎ−（４−アミジノフェニル）プロピオンアミド 二トリフルオロ酢酸塩の合成
工程１
３−（３−シアノフェノキシ）プロピオン酸 メチルエステル
水素化ナトリウム２４ｍｇ（０．６ｍｍｏｌ）をアクリル酸メチルエステル１０ｍｌ中撹拌し、３−ヒドロキシベンゾニトリル１ｇ（８．４ｍｍｏｌ）、ヒドロキノン２ｍｇを加えた。三日間加熱環流後、酢酸を加えて減圧濃縮した。酢酸エチルを加えて水、１規定水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物を得た。収量 ９９６ｍｇ（４．８５ｍｍｏｌ） 収率 ５８％
H-NMR(CDCl3)δ2.80(2H,t),3.77(3H,s),4.25(2H,t),7.14(1H,d),7.15(1H,s),7.26(1H,d),7.37(1H,t),
工程２
３−（３−シアノフェノキシ）プロピオニックアシッドの合成
３−（３−シアノフェノキシ）プロピオニックアシッド メチルエステル５００ｍｇ（２．４ｍｍｏｌ）を６規定塩酸４０ｍｌ中７０℃で３０分間加熱した。酢酸エチルで抽出し飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥して溶媒を留去し表題化合物を得た。
収量 ４７６ｍｇ（２．５ｍｍｏｌ） 収率 １００％
H-NMR(DMSO-d6)δ2.70(2H,t),4.23(2H,t),7.29(1H,d),7.38-7.48(2H,m),7.49(1H,t)
工程３
３−（３−シアノフェノキシ）−Ｎ−（４−シアノフェニル）プロピオンアミドの合成
３−（３−シアノフェノキシ）プロピオニックアシッド１２２ｍｇ（０．６４ｍｍｏｌ）、Ｎ−メチルモルホリン１５０ｍｇ（１．５ｍｍｏｌ）、クロロ蟻酸エチル７０ｍｇ（０．６４ｍｍｏｌ）、４−アミノベンゾニトリル８２ｍｇ（０．７ｍｍｏｌ）を用いて実施例６７工程３と同様にして表題化合物の粗製物を得た。これを酢酸エチル−ヘキサンを溶出溶媒とするシリカゲルクロマトグラフィーで精製した。
収量 ３６ｍｇ（０．１２ｍｍｏｌ） 収率 １９％
H-NMR(CD3OD)δ2.90(2H,t),4.40(2H,t),7.23-7.31(3H,m),7.44(1H,t),7.65-7.83(4H,m)
工程４
３−（３−アミジノフェノキシ）−Ｎ−（４−アミジノフェニル）プロピオンアミド 二トリフルオロ酢酸塩の合成
（３−シアノフェノキシ）−Ｎ−（４−シアノフェニル）プロピオンアミド３５ｍｇ（０．１２ｍｍｏｌ）を用いて実施例３工程３と同様にして表題化合物を得た。
収量 ８．４ｍｇ（０．０１５ｍｍｏｌ） 収率 １３％
MS(ESI,m/z)326(MH+)
H-NMR(DMSO-d6)δ2.90(2H,t),4.40(2H,t),7.32(1H,d),7.37-7.42(2H,m),7.54(1H,t),7.82(4H,s),9.00(2H,br),9.20(4H,br),9.30(2H,br),10.60(1H,s)
実施例６９
Ｎ−［３−（３−アミジノフェノキシメチル）］フェニル−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
の合成
工程１
３−（３−ニトロベンジルオキシ）ベンゾニトリルの合成
３−ニトロベンジルクロライド１．７０ｇ（１０．０ｍｍｏｌ）、３−シアノフェノール１．４８ｇ（１２．４ｍｍｏｌ）および炭酸カリウム３．５８ｇ（２５．９ｍｍｏｌ）をジメチルホルムアミド８０ｍｌに懸濁し、９５℃で終夜撹拌した。放冷後、水１５０ｍｌを加え析出した固体を濾過した。さらに固体を水１００ｍｌ続いて、酢酸エチル２０ｍｌで洗浄した。減圧下で乾燥し表題化合物を得た。
収量 ２．３２ｇ（９．１２ｍｍｏｌ） 収率 ９１．２％
H-NMR(DMSO-d6)δ5.38(2H,s),7.38-7.42(2H,m),7.48-7.59(2H,m),7.75(1H,dd),7.93(1H,dd),8.23(1H,dd),8.35(1H,d)
工程２
３−［３−アミノベンジルオキシ］ベンゾニトリルの合成
３−［３−ニトロベンジルオキシ］ベンゾニトリル２．３２ｇ（９．１２ｍｍｏｌ）、と亜鉛４．３８ｇを酢酸５０ｍｌに懸濁し４５℃で４時間撹拌した。不溶物を濾過後、濾液を留去しクロロホルム１００ｍｌと１規定水酸化ナトリウム水溶液５０ｍｌを加えて分液した後、常法に従って処理し表題化合物を得た。
収量 １．４２ｇ（６．３３ｍｍｏｌ） 収率 ６９．４％
H-NMR(DMSO-d6)δ5.03(2H,s),5.09(2H,brs),6.50(1H,dd),6.55(1H,d),6.63(1H,d),7.02(1H,dd),7.35(1H,dd),7.40(1H,dd),7.42(1H,d),7.43(1H,dd)
工程３
Ｎ−［３−（３−アミジノフェノキシメチル）フェニル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
３−［３−アミノベンジルオキシ］ベンゾニトリル２．４８ｇ（１１．１ｍｍｏｌ）、４−シアノ安息香酸１．１８ｇ（８．０２ｍｍｏｌ）を用いて実施例４工程１と同様にして縮合しＮ−［３−（３−シアノフェノキシメチル）］フェニル−４−シアノベンズアミドを得た後、精製することなく実施例１工程６と同様にして表題化合物を得た。
収量 ８９５ｍｇ（１．４５ｍｍｏｌ） 収率 １８．１％
MS(ESI,m/z)388(MH+)
H-NMR(DMSO-d6)δ5.24(2H,s),7.22(1H,d),7.25-7.32(6H,m),7.78(1H,d),8.00(2H,d),8.20(2H,d),9.38(2H,s),9.45(2H,s),9.62(2H,s),9.80(2H,s),10.60(1H,s)
実施例７０
Ｎ−［（１Ｒ）−１−（２−メチルプロピル）−２−（３−アミジノフェノキシ）エチル］−４−（ピロリジン−１−イル）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
［（１Ｒ）−２−クロロ−１−（２−メチルプロピル）エチル］カルバミン酸ｔ−ブチルの合成 Ｎ−ｔ−ブトキシカルボニル−Ｄ−ロイシン５ｇ（２１．６ｍｍｏｌ）を用い、クロロギ酸エチル２．４４ｇ（２２．５ｍｏｌ）、ジイソプロピルエチルアミン３．２１ｇ（２４．８ｍｍｏｌ）を用いＴＨＦ中５０ｍｌ中で対応する混合酸無水物とした後、水素化ホウ素ナトリウム２．１２ｇを用いて還元し（１Ｒ）−２−ヒドロキシ−１−（２−メチルプロピル）エチルカルバミン酸ｔ−ブチルの粗製物を得た。
H-NMR(CDCl3)δ0.92(3H,d),0.94(3H,d),1.27-1.38(2H,m),1.42(9H,s),1.60-1.73(1H,m),2.68-4.18(3H,m),4.67(1H,d)
この（１Ｒ）−２−ヒドロキシ−１−（２−メチルプロピル）エチルカルバミン酸ｔ−ブチルの粗製物をメタンスルホニルクロリド２．４７ｇ（２１．６ｍｍｏｌ）、ジイソプロピルエチルアミン４．５２ｇ（３５．０ｍｍｏｌ）を用い常法に従って反応させメシル体とし、塩化リチウム２．１５ｇ（５０．７ｍｏｌ）を用いてジメチルホルムアミド中１２０ｍｌで反応させ表題化合物を得た。
収量 ２．３５ｇ（９．９７ｍｍｏｌ）収率 ４６．２％
H-NMR(CDCl3)δ0.92(3H,d),0.94(3H,d),1.27-1.38(2H,m),1.42(9H,s),1.58-1.73(1H,m),2.88-4.18(3H,m),4.75(1H,d)
工程２
（１Ｒ）−２−（３−シアノフェノキシ）−１−（２−メチルプロピル）エチルカルバミン酸ｔ−ブチルの合成
（１Ｒ）−２−クロロ−１−（２−メチルプロピル）エチルカルバミン酸ｔ−ブチル２．３５ｇ（９．９７ｍｍｏｌ）、３−シアノフェノール２．４２ｇ（２０．３ｍｍｏｌ）および炭酸カリウム２．７２ｇ（１９．７ｍｍｏｌ）を用いジメチルホルムアミド中で反応させ常法に従って処理し表題化合物を得た。
収量 １．２７ｇ（３．９９ｍｍｏｌ） 収率 ４０．０％
H-NMR(CDCl3)δ0.91(3H,d),0.94(3H,d),1.42(9H,s),1.40-1.78(3H,m),3.88-4.09(3H,m),4.59-4.67(1H,m),7.10-7.42(4H,m)
工程３
Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−（２−メチルプロピル）エチル］−４−（ピロリジン−１−イル）ベンズアミド 二トリフルオロ酢酸塩の合成
（１Ｒ）−２−（３−シアノフェノキシ）−１−（２−メチルプロピル）エチルカルバミン酸ｔ−ブチル１．２７ｇ（３．９９ｍｍｏｌ）を用い実施例５９と同様の操作を行い表題化合物を得た。
収量 １７０ｍｇ（０．３２５ｍｍｏｌ） 収率 ８．１５％
H-NMR(DMSO-d6)δ0.88(3H,d),0.91(3H,d),1.41-1.78(3H,m),1.82-2.01(4H,m),3.15-3.30(4H,m),3.95(1H,dd),4.10(1H,dd),4.32-4.42(1H,d),6.55(2H,d),7.35(1H,d),7.38(1H,dd),7.40(1H,d),7.53(1H,dd),7.65(1H,dd),7.93(1H,d),9.21(2H,s),9.27(2H,s)
実施例７１
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸モノエチル 二トリフルオロ酢酸塩 および
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチル 二トリフルオロ酢酸塩の合成
工程１
４−ヒドロキシピペリジン−１−カルボン酸ベンジルの合成
４−ヒドロキシピペリジン２５．０ｇ（２４７ｍｍｏｌ）をジクロロメタン８００ｍｌに溶解し、０℃でベンジルオキシカルボニルクロライド３８ｍｌ（２６６ｍｍｏｌ）、トリエチルアミン７５ｍｌ（５３８ｍｍｏｌ）を加えた後、室温で１５時間撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し油状残渣を得た。このものは精製することなく次の反応に用いた。
収量 ４４．６ｇ（２０３ｍｍｏｌ） 収率 ８２％
工程２
（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−ヒドロキシフェニル）プロピオン酸メチルの合成
Ｌ−チロシンメチルエステル塩酸塩１５．２ｇ（６５．６ｍｍｏｌ）をジクロロメタン２００ｍｌに溶解し、室温でトリエチルアミン２０ｍｌ（１４３ｍｍｏｌ）、ジ−ｔ−ブチルジカーボネート１３．１ｇ（６０．０ｍｍｏｌ）をジクロロメタン５０ｍｌに溶解したものを加え、１５時間撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し油状残渣を得た。このものは精製することなく次の反応に用いた。
収量 １９．２ｇ（６５．２ｍｍｏｌ） 収率 ９９％
工程３
（２Ｓ）−３−［４−［１−（ベンジロキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロピオン酸メチルの合成
４−ヒドロキシピペリジン−１−カルボン酸ベンジル１８．９ｇ（８６．２ｍｍｏｌ）、（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−ヒドロキシフェニル）プロピオン酸メチル２５．４ｇ（８６．２ｍｍｏｌ）、トリフェニルホスフィン２７．１ｇ（１０３．４ｍｍｏｌ）をテトラヒドロフラン５００ｍｌに溶解しアゾジカルボン酸ジエチル３７．５ｇ（８６．２ｍｍｏｌ）を室温で加え、１５時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ３２．１ｇ（６２．６ｍｍｏｌ） 収率 ７３％
H-NMR(CDCl3)δ1.42(9H,s),1.70-1.84(2H,m),1.86-2.00(2H,m),2.91-3.10(2H,m),3.38-3.53(2H,m),3.70(3H,s),3.71-3.82(2H,m),4.40-4.44(1H,m)4.45-4.60(1H,m),4.93-5.00(1H,m),5.18(2H,s),6.92(2H,d),7.02(2H,d),7.13-7.21(5H,m)
工程４
４−［４−［（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−ヒドロキシプロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジルの合成
（２Ｓ）−３−［４−［１−（ベンジロキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロピオン酸メチル１０．４ｇ（２０．３ｍｍｏｌ）をテトラヒドロフラン３０ｍｌ、メタノール３０ｍｌに溶解し、０℃で水素化ホウ素ナトリウム２．４４ｇ（６４．５ｍｍｏｌ）を加え、室温に戻して１５時間撹拌後、０℃で再び水素化ホウ素ナトリウム０．８２ｇ（２１．７ｍｍｏｌ）を加え、室温に戻して更に２時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ９．４５ｇ（１９．５ｍｍｏｌ） 収率 ９６％
H-NMR(CDCl3)δ1.44(9H,s),1.68-1.82(2H,m),1.84-1.98(2H,m),2.78(2H,d),3.29-3.95(7H,m),4.40-4.44(1H,m),5.14(2H,s),6.92(2H,d),7.12(2H,d),7.28-7.40(5H,m)
工程５
４−［４−［（２Ｓ）−３−クロロ−２−（ｔ−ブトキシカルボニルアミノ）プロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジルの合成
４−［４−［（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−ヒドロキシプロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジル５．５ｇ（１１．３ｍｍｏｌ）をジクロロメタン６０ｍｌに溶解し、０℃でトリエチルアミン３．２ｍｌ（２２．６ｍｍｏｌ）、メタンスルホニルクロリド１．９５ｇ（１７．０ｍｍｏｌ）を加えた。４時間撹拌後、ジクロロメタンを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた残留物をジメチルホルムアミド１２０ｍｌに溶解し、リチウムクロリド２．５７ｇ（６０．６ｍｍｏｌ）を加え、５０℃で１５時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ２．６０ｇ（５．１６ｍｍｏｌ） 収率 ４５％
H-NMR(CDCl3)δ1.44(9H,s),1.63-1.82(2H,m),1.83-2.00(2H,m),2.91-3.10(2H,m),2.83(2H,d),3.40-3.54(3H,m),3.57-3.63(1H,m),3.66-3.80(3H,m),4.40-4.52(1H,m),5.14(2H,s),6.92(2H,d),7.16(2H,d),7.13-7.21(5H,m)
工程６
３−［（２Ｓ）−３−［４−［１−（ベンジロキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリルの合成
３−［４−［（２Ｓ）−３−クロロ−２−（ｔ−ブトキシカルボニルアミノ）プロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジル６．４ｇ（１２．７ｍｍｏｌ）をジメチルホルムアミド７０ｍｌに溶解し、３−シアノフェノール２．２７ｇ（１９．１ｍｍｏｌ）、炭酸カリウム３．５１ｇ（２５．４ｍｍｏｌ）を加え、７０℃で１５時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ５．０ｇ（８．５４ｍｍｏｌ） 収率 ６７％
H-NMR(CDCl3)δ1.44(9H,s),1.66-1.83(2H,m),1.84-2.00(2H,m),2.50-2.60(1H,m),2.82-2.93(1H,m),3.40-3.53(3H,m),3.58-3.63(1H,m),3.65-3.80(3H,m),4.40-4.53(1H,m),5.14(2H,s)6.92(2H,d),7.16(2H,d),7.13-7.21(5H,m)
工程７
３−［（２Ｓ）−３−［４−［１−（ベンジロキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（４−ヨードベンゼンスルホニルアミノ）プロポキシ］ベンゾニトリルの合成 ３−［（２Ｓ）−３−［４−［１−（ベンジロキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル２．５４ｇ（４．３４ｍｍｏｌ）に、４規定塩化水素のジオキサン溶液２５ｍｌ、ジオキサン１２．５ｍｌを加えた。室温で２４時間撹拌後、溶媒を減圧留去して得た残渣をジメチルホルムアミド４０ｍｌに溶解した。ジイソプロピルエチルアミン１．７７ｍｌ（１３．０ｍｍｏｌ）、４−ヨードベンゼンスルホニルクロリド１．９７ｇ（６．５１ｍｍｏｌ）を０℃で加えた。３０分後、室温に戻して１９時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ２．５０ｇ（３．３９ｍｍｏｌ） 収率 ７８％
H-NMR(CDCl3)δ1.62-1.83(2H,m),1.63-2.00(2H,m),2.62-2.80(1H,m),2.83-3.00(1H,m),3.40-3.53(2H,m),3.62-3.80(3H,m),3.81-4.00(2H,m),4.40-4.45(1H,m),4.40-4.45(1H,m),5.14(2H,s),5.20-5.36(1H,m),6.73(2H,d),6.90(2H,d),7.01(2H,d),7.24-7.44(9H,m),7.70(2H,d)
工程８
４−［（１Ｓ）−２−（３−シアノフェノキシ）−１−［４−［（１−ベンジルオキシカルボニル−４−ピペリジル）オキシ］フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチルの合成
３−［（２Ｓ）−３−［４−［（１−ベンジルオキシカルボニル−４−ピペリジル）オキシ］フェニル］−２−（４−ヨードベンゼンスルホニルアミノ）プロポキシ］ベンゾニトリル３１０ｍｇ（０．４２ｍｍｏｌ）に、ホスホン酸ジエチル０．５９ｍｌ（０．４６ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム２４ｍｇ（０．０２ｍｍｏｌ）、トリエチルアミン２０ｍｌを加え、アルゴン存在下、９０℃で４時間撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 １３９ｍｇ（０．１８ｍｍｏｌ） 収率 ４３％
H-NMR(CDCl3)δ1.34(6H,t),1.68-1.83(2H,m),1.84-2.00(2H,m),2.76-2.94(2H,m),3.40-3.53(2H,m),3.70-3.81(3H,m),3.82-3.95(2H,m),4.04-4.25(4H,m),4.38-4.52(1H,m),5.14(2H,s),6.76(2H,d),6.92(2H,d),6.95-7.05(3H,m),7.32-7.39(5H,m),7.42-7.51(1H,m)7.63-7.71(1H,m),7.84(2H,d),7.87(2H,d)
工程９
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸モノエチル 二トリフルオロ酢酸塩および
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチル 二トリフルオロ酢酸塩の合成 ４−［（１Ｓ）−２−（３−シアノフェノキシ）−１−［４−［（１−ベンジルオキシカルボニル−４−ピペリジル）オキシ］フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチル１３９ｍｇ（０．１８ｍｍｏｌ）を４規定塩化水素のジオキサン溶液４．５ｍｌに溶解し、塩化水素を３０％含有する（ｗ／ｖ）エタノール０．５ｍｌを加えた。室温で９６時間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液２４ｍｌに溶解して室温で２４時間撹拌した。溶媒を留去して得られた残留物を０℃で２０％臭化水素を含む酢酸１８ｍｌを加え１時間撹拌後、室温に戻して７時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸モノエチル 二トリフルオロ酢酸塩収量 ２９ｍｇ（０．０３ｍｍｏｌ） 収率 １９％
MS(ESI,m/z)579(MH+)
H-NMR(DMSO-d6)δ1.18(3H,t),1.68-1.90(2H,m),2.00-2.18(2H,m),2.56-2.70(1H,m),2.80-2.92(1H,m),3.01-3.21(2H,m),3.21-3.36(2H,m),3.64-3.76(1H,m),3.82(2H,q),3.96(2H,d),4.53-4.64(1H,m),6.80(2H,d),7.03(2H,d),7.08(1H,br),7.22(1H,br),7.37(1H,dd),7.46(1H,dd)7.68(2H,d),7.70(2H,br),8.21(1H,dd),8.38-8.54(1H,m),9.00(2H,br),9.33(2H,br)
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチル 二トリフルオロ酢酸塩 収量 １９ｍｇ（０．０２ｍｍｏｌ） 収率 １２％
MS(ESI,m/z)645(MH+)
H-NMR(DMSO-d6)δ1.24(6H,t),1.70-1.87(2H,m),2.01-2.14(2H,m),2.54-2.69(1H,m),2.77-2.93(1H,m),2.98-3.18(2H,m),3.20-3.33(2H,m),3.62-3.74(1H,m),3.97(2H,d),4.04(4H,dq),4.53-4.64(1H,m),6.80(2H,d),7.03(2H,dd),7.08(1H,br),7.26(1H,br),7.37(1H,dd),7.48(1H,dd)7.74(2H,d),7.76(2H,br),8.31(1H,dd),8.38-8.54(1H,m),9.02(2H,br),9.27(2H,br)
実施例７２
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−［（１−アセトイミドイル−４−ピペリジル）オキシ］フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチル 二トリフルオロ酢酸塩の合成
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチル 二トリフルオロ酢酸塩１９ｍｇ（０．０２ｍｍｏｌ）を出発原料とし、実施例４４と同様の操作に従って表題化合物を得た。収量 １１ｍｇ（０．０１ｍｍｏｌ） 収率 ５５％
MS(ESI,m/z)686(MH+)
H-NMR(DMSO-d6)δ1.14(6H,t),1.60-1.84(2H,m),1.93-2.14(2H,m),2.28(3H,s),2.54-2.71(1H,m),2.78-2.93(1H,m),3.46-3.60(2H,m),3.62-3.77(3H,m),3.80(4H,q),3.98(2H,d),4.58-4.67(1H,m),6.82(2H,d),7.05(2H,d),7.08(1H,br),7.23(1H,br),7.35(1H,d),7.47(1H,dd)7.67(4H,dd),8.21(1H,dd),8.73(1H,br),9.08(2H,br),9.10(1H,br),9.33(2H,br)
実施例７３
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−［（１−アセトイミドイル−４−ピペリジル）オキシ］フェニルメチル］エチル］スルファモイル］フェニルホスホン酸モノエチル 二トリフルオロ酢酸塩の合成
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−（４−ピペリジルオキシ）フェニルメチル］エチル］スルファモイル］フェニルホスホン酸モノエチル２９ｍｇ（０．０３ｍｍｏｌ）を出発原料とし、実施例４４と同様の操作に従って表題化合物を得た。
収量 １３ｍｇ（０．０１ｍｍｏｌ） 収率 ４３％
MS(ESI,m/z)658(MH+)
H-NMR(DMSO-d6)δ1.24(3H,t),1.67-1.85(2H,m),1.99-2.15(2H,m),2.29(3H,s),2.56-2.70(1H,m),2.79-2.95(1H,m),3.47-3.61(2H,m),3.62-3.85(3H,m),3.97(2H,d),4.03(2H,q),4.59-4.71(1H,m),6.82(2H,d),7.05(2H,d),7.09(1H,br),7.27(1H,br),7.42(1H,d),7.48(1H,dd)7.73(2H,d),7.76(2H,br),8.32(1H,dd),8.57(1H,br),9.06(2H,br),9.13(1H,br),9.32(2H,br)
実施例７４
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−［（１−アセトイミドイル−４−ピペリジル）オキシ］フェニルメチル］エチル］スルファモイル］フェニルホスホン酸 二トリフルオロ酢酸塩の合成
［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［４−［（１−アセトイミドイル−４−ピペリジル）オキシ］フェニルメチル］エチル］スルファモイル］フェニルホスホン酸ジエチル 二トリフルオロ酢酸塩８ｍｇ（０．００９ｍｍｏｌ）に濃塩酸１ｍｌを加え、１３０℃で４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ３ｍｇ（０．００４ｍｍｏｌ） 収率 ３９％
MS(ESI,m/z)630(MH+)
H-NMR(DMSO-d6)δ1.62-1.83(2H,m),1.94-2.12(2H,m),2.28(3H,s),2.53-2.70(1H,m),2.78-2.86(1H,m),3.48-3.63(2H,m),3.65-3.80(3H,m),3.95(2H,d),4.58-4.70(1H,m),6.82(2H,d),7.03(2H,d),7.07(1H,br),7.22(1H,br),7.34(1H,d),7.46(1H,dd)7.66(2H,d),7.78(2H,br),8.16(1H,d),8.66(1H,br),9.04(2H,br),9.09(1H,br),9.30(2H,br)
実施例７５
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［（４−アミジノフェニル）メチル］エチル］スルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
工程１
［（１Ｓ）−２−ヒドロキシ−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチルの合成
氷冷下、メタノール３ｍｌに塩化チオニル０．５６ｍｌ（７．７３ｍｍｏｌ）を加えた後、Ｌ−４−ヨードフェニルアラニン４５０ｍｇ（１．５６ｍｍｏｌ）を加え２時間加熱環流した。溶媒を留去して得られた残留物にＮ−メチルモルホリン０．５２ｍｌ（４．６８ｍｍｏｌ）、ジ−ｔ−ブチルカルボネート４４３ｍｇ（２．０３ｍｍｏｌ）、ジクロロメタン１０ｍｌを加え１９時間撹拌した。反応液を水で希釈し、ジクロロメタンにて抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られた残留物にメタノール３ｍｌ、テトラヒドロフラン３ｍｌを加え、氷冷下、水素化ホウ素ナトリウム１４３ｍｇ（３．７８ｍｍｏｌ）を加え１７時間撹拌した。１規定塩酸に反応液をゆっくりあけ、酢酸エチルで抽出した。有機層を水、１規定塩酸、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥、溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２４０ｍｇ（０．６４ｍｍｏｌ） 収率 ４１％
H-NMR(CDCl3)δ1.42(9H,s),3.48-3.77(2H,m),2.59(2H,d),3.79-3.91(2H,m),4.63-4.78(1H,m),6.97(2H,d),7.64(2H,d)
工程３
［（１Ｓ）−２−クロロ−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチルの合成 ［（１Ｓ）−２−ヒドロキシ−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチル３６０ｍｇ（０．９６ｍｍｏｌ）のジクロロメタン５ｍｌ中に氷冷下、トリエチルアミン０．２７ｍｌ（１．９２ｍｍｏｌ）、メタンスルホニルクロライド１６５ｍｇ（１．４４ｍｍｏｌ）を加え３０分撹拌後、室温に戻して１５時間撹拌した。反応液を水で希釈し、ジクロロメタンにて抽出した。有機層を１規定塩酸、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後し溶媒を減圧留去して得られた残留物にジメチルホルムアミド１０ｍｌ、塩化リチウム２０３ｍｇ（４．８ｍｍｏｌ）を加え５０℃で１９時間撹拌した。反応液を水で希釈し、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ２３７ｍｇ（０．６０ｍｍｏｌ） 収率 ６３％
H-NMR(CDCl3)δ1.43(9H,s),2.80-2.93(2H,m),3.48(1H,dd),3.62(1H,dd),4.00-4.18(1H,m),7.00(2H,d),7.63(2H,d)
工程３
［（１Ｓ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチルの合成
［（１Ｓ）−２−クロロ−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチル２３７ｍｇ（０．６０ｍｍｏｌ）、ジメチルホルムアミド５ｍｌに、３−シアノフェノール１０７ｍｇ（０．９０ｍｍｏｌ）、炭酸カリウム１６５ｍｇ（１．２ｍｍｏｌ）を加え７０℃で１９時間撹拌した。反応液を水で希釈し、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。収量 ２８２ｍｇ（０．５９ｍｍｏｌ） 収率 ６３％
H-NMR(CDCl3)δ1.43(9H,s),2.93(2H,d),3.84-3.94(2H,m),4.73-4.89(1H,m),6.94(2H,d),7.09(2H,d),7.13(1H,d),7.38(1H,dd),7.60(2H,d)
工程４
４−［（１Ｓ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］スルファモイル］安息香酸ｔ−ブチルの合成
［（１Ｓ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチル１１７ｍｇ（０．２４ｍｍｏｌ）を４規定塩化水素のジオキサン溶液１．３ｍｌ、ジオキサン０．６３ｍｌに溶解し、３時間撹拌した。溶媒を留去して得られた残留物をジメチルホルムアミド５ｍｌに溶解させ、氷冷下、ジイソプロピルエチルアミン０．１３ｍｌ（０．７３ｍｍｏｌ）、４−クロロスルホニル安息香酸ｔ−ブチル１３５ｍｇ（０．４９ｍｍｏｌ）を加え３０分撹拌した。室温に戻して１９時間撹拌した。反応液を水で希釈し、酢酸エチルにて抽出した。（なお４−クロロスルホニル安息香酸ｔ−ブチルはクロロスルホニル安息香酸、イソブテン、濃硫酸を用いてジクロロメタン中で反応させ常法に従って処理して得た）。有機層を水、飽和食塩水で順次洗浄後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ５０ｍｇ（０．０８ｍｍｏｌ） 収率 ３３％
H-NMR(CDCl3)δ1.63(9H,s),2.71-2.82(1H,m),2.86-2.99(1H,m),5.15-5.28(1H,m),7.07(2H,br),7.20(2H,d),7.27(1H,dd),7.34(1H,dd),7.45(2H,d),7.69(2H,d),7.98(2H,d)
工程５
４−［（１Ｓ）−２−（３−シアノフェノキシ）−１−（４−シアノベンジル）エチル］スルファモイル］安息香酸ｔ−ブチルの合成
４−［（１Ｓ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］スルファモイル］安息香酸ｔ−ブチル５０ｍｇ（０．０８ｍｍｏｌ）をＮ−メチル−２−ピロリドン０．５ｍｌに溶解させ、シアン化銅（Ｉ）１１ｍｇ（０．０１ｍｍｏｌ）を加え、アルゴン存在下、１３０℃で７時間撹拌した。反応液をシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２１ｍｇ（０．０４ｍｍｏｌ） 収率 ３３％
H-NMR(CDCl3)δ1.63(9H,s),2.82-3.10(1H,m),3.90(2H,br),5.06-5.13(1H,m),7.01(2H,br),7.15(2H,d),7.28(1H,dd),7.37(1H,dd),7.47(2H,d),7.74(2H,d),7.98(2H,d)
工程６
４−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−［（４−アミジノフェニル）メチル］エチル］スルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
４−［（１Ｓ）−２−（３−シアノフェノキシ）−１−（４−シアノベンジル）エチル］スルファモイル］安息香酸ｔ−ブチル２１ｍｇ（０．０４ｍｍｏｌ）を出発原料とし、同様の操作に従って表題化合物を得た。
収量 ３ｍｇ（０．００４ｍｍｏｌ） 収率 １０％
MS(ESI,m/z)496(MH+)
H-NMR(DMSO-d6)δ2.42-2.60(1H,m),2.72-2.84(1H,m),3.48-3.61(1H,m),3.77(2H,dd),6.88(2H,dd),7.01(1H,br),7.08(2H,d),7.12(1H,dd),7.23(1H,t),7.33(2H,d),7.38(1H,br),7.60(2H,d),8.08-8.15(1H,m),8.63(2H,br),8.73(1H,br),8.93(2H,br),9.02(2H,br)
実施例７６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−［（ピペリジン−４−イル）オキシ］ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンズアミドの合成
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸２１１．２ｍｇ（０．６５ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル塩酸塩１２９．２ｍｇ（０．６５ｍｍｏｌ）を出発原料とし、実施例１工程４と同様の操作により表題化合物を得た。
収量 １６７ｍｇ（０．３６ｍｍｏｌ） 収率 ５５％
H-NMR(CDCl3)δ1.50(9H,s),1.65-1.80(2H,m),1.85-2.00(2H,m),3.30-3.40(2H,m),3.60-3.75(2H,m),3.90(2H,dt),4.20(2H,t),4.55(1H,m),6.45(1H,t),6.94(2H,d),7.15(1H,d),7.17(1H,s),7.26(1H,d),7.38(1H,t),6.74(2H,d)
工程２
Ｎ−［２−（３−シアノフェノキシ）エチル］−Ｎ−ベンジル−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イル）オキシベンズアミドの合成
水素化ナトリウム（油性６０％）２３６ｍｇ（５．９１ｍｍｏｌ）をジメチルホルムアミド中氷冷下撹拌した。Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イル）オキシベンズアミド２．６７ｇ（５．９１ｍｍｏｌ）を少量のジメチルホルムアミドに溶解して加えた。水素の発生が終わった後にベンジルブロミド１．４ｍｌ（１１．８ｍｍｏｌ）を加えた後、室温で２時間撹拌した。溶媒を減圧留去した後に１規定塩化水素を加え酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量２．８５ｇ（５．２６ｍｍｏｌ） 収率 ８９％
H-NMR(CDCl3)δ1.43(9H,s),1.72-1.80(2H,m),1.85-1.93(2H,m),3.23-3.38(2H,m),3.60-3.70(2H,m),3.72-3.81(2H,m),4.15-4.22(2H,m),4.47-4.50(1H,m),4.77(2H,brs),6.88(1H,d),7.09(1H,m),7.25(1H,brs),7.26-7.50(7H,m),7.58(1H,d),7.68(1H,t),8.01(1H,s)
工程３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−［（ピペリジン−４−イル）オキシ］ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−Ｎ−ベンジル−４−（１−ｔ−ブトキシカルボニルピペリジン−４−イル）オキシベンズアミド２．８５ｇ（５．２６ｍｍｏｌ）を４規定塩化水素を含むジオキサン５ｍｌ中撹拌し、そこへ塩化水素を３０％含む（ｗ／ｖ）エタノール５ｍｌを加えて室温で５日間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１５ｍｌに溶解して室温で１日間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量１．２５ｇ（１．７８ｍｍｏｌ） 収率 ３４％
MS(ESI,m/z)473(MH+)
H-NMR(DMSO-d6)δ1.79-1.83(2H,m),2.05-2.11(2H,m),3.06-3.11(2H,m),3.22-3.27(2H,m),3.63-3.68(2H,m),4.15-4.29(2H,m),4.69-4.77(3H,m),7.04(2H,d),7.20-7.60(10H,m),7.50(1H,t),8.60(2H,brs),9.26(4H,d)
実施例７７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−（１−アセチル−ピペリジン−４−イル）オキシベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−［（ピペリジン−４−イル）オキシ］ベンズアミド 二トリフルオロ酢酸塩１８０ｍｇ（０．２５７ｍｍｏｌ）、トリエチルアミン０．１２ｍｌ（０．８４８ｍｍｏｌ）をピリジン１ｍｌ中氷冷下撹拌し、そこへアセチルクロライド０．０２ｍｌ（０．２８３ｍｍｏｌ）をゆっくりと加え３日間撹拌した。室温に戻した後、溶媒を留去し、得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ７３．５ｍｇ（０．１２ｍｍｏｌ） 収率 ４６％
MS(ESI,m/z)515(MH+)
H-NMR(DMSO-d6)δ1.41-1.62(2H,m),1.85-2.00(2H,m),2.01(3H,s),3.23(2H,dt),3.60-3.65(2H,m),3.80-3.90(1H,m),4.20-4.30(2H,m),4.60-4.70(2H,m),4.75(2H,brs),7.03(2H,d),7.20-7.43(10H,m),7.52(1H,t),9.21(4H,d)
実施例７８
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−［１−（アミノアセチル）−ピペリジン−４−イル］オキシベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−ｔ−ブトキシカルボニルグリシン４０ｍｇ（０．３１４ｍｍｏｌ）をジメチルホルムアミド中撹拌し、氷冷下トリエチルアミン０．１ｍｌ（０．６９ｍｍｏｌ）、クロロ蟻酸エチル０．０３ｍｌ（０．３１４ｍｍｏｌ）を加え５分間撹拌した後、Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−［（ピペリジン−４−イル）オキシ］ベンズアミド 二トリフルオロ酢酸塩２２０ｍｇ（０．３１４ｍｍｏｌ）を加えた。室温に戻して４時間撹拌した後、溶媒を留去して粗製物を得た。この粗製物を４規定塩化水素を含むジオキサン０．５ｍｌ中２８時間室温で撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ６１．６ｍｇ（０．０８１３ｍｍｏｌ） 収率 ２６％
MS(ESI,m/z)530(MH+)
H-NMR(DMSO-d6)δ1.50-1.70(2H,m),1.91-2.10(2H,m),3.05-3.10(1H,m),3.20-3.40(2H,m),3.52-3.70(3H,m),3.80-4.00(2H,m),4.23(2H,m),4.72(2H,brs),7.05(2H,d),7.20-7.52(10H,m),7.53(1H,t),8.03(3H,brs),9.28(4H,d)
実施例７９
３−［４−アミジノ−２−［２−［４−（１−アセトイミドイル−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソプロピオン酸 二トリフルオロ酢酸塩の合成
工程１
３−ヒドロキシ−４−ヨード安息香酸の合成
３−ヒドロキシ安息香酸３０．０ｇ（２１７ｍｍｏｌ）を酢酸２００ｍｌに溶解し、一塩化ヨウ素５３．０ｇ（３２６ｍｍｏｌ）を室温で加えた。４５℃で１５時間撹拌後、溶媒を減圧留去して得た残渣を１％チオ硫酸ナトリウム水溶液５００ｍｌで２回、水５００ｍｌで２回洗浄し、８０℃で減圧乾固させることで、表題化合物を得た。
収量 １７．２ｇ（６５．２ｍｍｏｌ） 収率 ３０％
MS(FAB,m/z)265(MH+)
H-NMR(DMSO-d6)δ7.13(1H,dd),7.43(1H,d),7.80(1H,d)
工程２
３−ヒドロキシ−４−ヨードベンゾニトリルの合成
３−ヒドロキシ−４−ヨード安息香酸２２．３ｇ（８９．７ｍｍｏｌ）をテトラヒドロフラン３００ｍｌに溶解したものにクロロギ酸エチル１９．７ｍｌ（２０６ｍｍｏｌ）、トリエチルアミン２８．７ｍｌ（２０６ｍｍｏｌ）を０℃で加えた。１５分撹拌後、生成したトリエチルアミン塩酸塩を濾別し、アンモニアをバブリングして得られたテトラヒドロフラン溶液３００ｍｌに、濾液を０℃で加えた。室温で１０時間撹拌後、溶媒を減圧留去して得られた残留物をジオキサン４５０ｍｌに溶解し無水トリフルオロメタンスルホン酸１７．４ｍｌ（１１７ｍｍｏｌ）、ピリジン２１．８ｍｌ（２６９ｍｍｏｌ）を０℃で加えた。室温で１８時間撹拌後、溶媒を減圧留去して得られた残留物をクロロホルムを抽出溶媒とし常法に従って処理し油状残渣を得た。得られた残留物をテトラヒドロフラン：メタノール（１：１）１８０ｍｌに溶解したものに１規定水酸化ナトリウム水溶液９０ｍｌ（９０．０ｍｍｏｌ）を室温で加えた。そのまま４時間撹拌後、溶媒を減圧留去し、得られた残留物をジクロロメタンで洗浄した。続いて、１規定塩化水素で酸性とし酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ９．２９ｇ（３７．９ｍｍｏｌ） 収率 ４２％
MS(FAB,m/z)246(MH+)
H-NMR(CDCl3)δ5.63(1H,br),6.96(1H,dd),7.23(1H,d),7.79(1H,d)
工程３
３−（２−アミノエトキシ）−４−ヨードベンゾニトリル塩酸塩の合成
３−ヒドロキシ−４−ヨードベンゾニトリル、ｔ−ブチル（２−クロロエチル）カルバマートを出発原料とし、実施例１の工程２及び工程３と同様の操作に従い表題化合物を得た。なおｔ−ブチル（２−クロロエチル）カルバマートは２−クロロエチルアミン塩酸塩を用いて実施例１工程１と同様にして得た。
工程４
Ｎ−［２−（５−シアノ−２−ヨードフェノキシ）エチル］−４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンズアミドの合成
３−（２−アミノエトキシ）−４−ヨードベンゾニトリル 塩酸塩２．２８ｇ（７．０３ｍｍｏｌ）、４−［（１−ｔ−ブトキシカルボニル−４−ピペリジル）オキシ］安息香酸２．９０ｇ（９．０２ｍｍｏｌ）、ジイソプロピルエチルアミン１１．１ｇ（８５．９ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３．０２ｇ（１５．８ｍｍｏｌ）および４−ジメチルアミノピリジン０．６２ｇ（５．０７ｍｍｏｌ）をジメチルホルムアミド８０ｍｌに溶解し、室温で終夜撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２．７２ｇ（４．６０ｍｍｏｌ） 収率 ６５．４％
H-NMR(CDCl3)δ1.43(9H,s),1.62-1.82(2H,m),1.89-2.00(2H,m),3.30-3.40(2H,m),3.62-3.78(2H,m),3.95(2H,dt),4.22(2H,t),4.55(1H,m),6.64(1H,t),6.94(2H,d),7.01(1H,d),7.03(1H,dd),7.78(2H,d),7.89(1H,d)
工程５
２−アセチルアミノ−３−［４−シアノ−２−［２−［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチルの合成
Ｎ−［２−（５−シアノ−２−ヨードフェノキシ）エチル］−４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンズアミド２．７２ｇ（４．６０ｍｍｏｌ）、２−アセトアミノアクリル酸メチル１．３２ｇ（９．２２ｍｍｏｌ）をアセトニトリル８０ｍｌに溶解し、酢酸パラジウム（ＩＩ）２７２ｍｇ（１．２１ｍｍｏｌ）、トリ−ｏ−トリルホスフィン６３０ｍｇ（２．０７ｍｍｏｌ）、トリブチルアミン１．７１ｇ（９．２３ｍｍｏｌ）を加え３日加熱環流した。溶媒を留去し、酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 １．１２ｇ（１．８５ｍｍｏｌ） 収率 ４０．２％
H-NMR(CDCl3)δ1.45(9H,s),1.65-1.80(2H,m),1.85-2.00(2H,m),2.02(3H,s),3.30-3.40(2H,m),3.60-3.75(2H,m),3.80(3H,s),4.35(2H,t),4.55(1H,m),6.82(2H,d),6.99(1H,t),7.18-7.22(2H,m),7.33(1H,s),7.44(1H,s),7.69(2H,d),7.87(1H,d)
工程６
３−［４−アミジノ−２−［２−［４−（１−アセトイミドイル−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソプロピオン酸 二トリフルオロ酢酸塩の合成
２−アセチルアミノ−３−［４−シアノ−３−［２−［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチル１．１２ｇ（１．８５ｍｍｏｌ）を４規定塩化水素のジオキサン溶液５０ｍｌに溶解し、エタノール５ｍｌを加え室温で１０日撹拌した。溶媒を留去し得られた残渣をアンモニアを２０％含有する（ｗ／ｖ）エタノール溶液８０ｍｌに溶解し、室温で４日撹拌した。溶媒を留去し、得られた残留物を、エチルアセトイミダート塩酸塩２．２３ｇ（１８．０ｍｍｏｌ）、トリエチルアミン１６．０ｇ（１５８ｍｍｏｌ）をエタノール１００ｍｌに溶解し、３０℃で４日撹拌した。溶媒を留去し得られた粗製物をトリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒（４ １）５０ｍｌに溶解しオクタドデシル基化学結合型シリカゲルを充填剤（ＬｉＣｈｒｏｐｒｅｐ ＲＰ−１８ ３７ｘ４４０ｍｍ）とする逆相中圧分取クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出した。凍結乾燥により溶媒を除いて得た残渣を６規定塩酸５０ｍｌに溶解し８０℃で２時間撹拌した。溶媒を留去し得られた粗製物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １２３ｍｇ（０．１６７ｍｍｏｌ） 収率 ９．０％
MS(ESI,m/z)510(MH+)
H-NMR(DMSO-d6)δ1.65-1.85(2H,m),2.02-2.19(2H,m),2.25(3H,s),3.58-3.82(6H,m),4.23(2H,s,keto form),4.30(2H,t),4.79(1H,m),6.80(1H,s,enol form),7.07(2H,d),7.38-7.47(2H,m),7.83(2H,d),8.33(1H,d),8.55-8.67(2H,m),9.05-9.34(5H,brm),9.75(1H,br,enol form)
実施例８０
３−［４−アミジノ−２−［２−［４−（ジメチルカルバモイル）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（２−ヨード−５−シアノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルカルバモイル）ベンズアミドの合成
４−ジメチルカルバモイル安息香酸６００ｍｇ（３．１ｍｍｏｌ）、トリエチルアミン１．２５ｇをジメチルホルムアミド中撹拌した。そこへ氷冷下クロロ蟻酸エチル３３６ｍｇ（３．１ｍｍｏｌ）を加え５分撹拌した後、３−（２−アミノエトキシ）−４−ヨードベンゾニトリル一塩酸塩を加えた。室温に戻し２時間撹拌後、１規定塩酸を加えて酢酸エチル抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を留去して得られた残留物を酢酸エチルで洗浄し、表題化合物を得た。またこの洗液の溶媒留去後の残留物をシリカゲルクロマトグラフィー（酢酸エチル−メタノール）で精製することによりさらに表題化合物を得た。
収量 計９８３ｍｇ（２．１ｍｍｏｌ） 収率 ６８％
H-NMR(DMSO-d6)δ2.87(3H,br),3.00(3H,br),3.65(2H,dt),4.27(2H,t),7.17(1H,d),7.47(2H,d),7.52(1H,s),7.88(2H,d),7.98(1H,d),8.67(1H,br)
工程２
２−アセチルアミノ−３−［４−シアノ−２−［２−［４−（ジメチルカルバモイル）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチルの合成
［２−（２−ヨード−５−シアノフェノキシ）エチル］−４−（Ｎ、Ｎ−ジメチルカルバモイル）ベンズアミド９６８ｍｇ（２．０９ｍｍｏｌ）、２−（アセチルアミノ）アクリル酸メチル６００ｍｇ（４．１８ｍｍｏｌ）、酢酸パラジウム（II）９３ｍｇ（０．３８ｍｍｏｌ）、トリ−ｏ−トリルホスフィン５４８ｍｇ（１．８ｍｍｏｌ）、トリブチルアミン７７５ｍｇ（４．１８ｍｍｏｌ）をアセトニトリル中２日間加熱還流した。溶媒を留去し、メタノールを加えてセライト濾過をした後、溶媒を留去した。残留物に１規定塩酸を加えて酢酸エチル抽出し有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を留去した。得られた残留物をシリカゲルクロマトグラフィー（酢酸エチル−メタノール）で精製することによりさらに表題化合物を得た。
収量 ６２９ｍｇ（１．３ｍｍｏｌ） 収率 ６２％
H-NMR(DMSO-d6)δ1.95(3H,s),2.90(3H,s),3.00(3H,s),3.60-3.70(5H,m),4.30(2H,t),7.21(1H,s),7.43(1H,d),7.47(2H,d),7.63(1H,s),7.67(1H,d),7.87(2H,d),8.75(1H,t),9.65(1H,s)
工程３
３−［４−アミジノ−２−［２−［４−（ジメチルカルバモイル）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 トリフルオロ酢酸塩の合成
２−アセチルアミノ−３−［４−シアノ−２−［２−［４−（ジメチルカルバモイル）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチル６２０ｍｇ（１．３ｍｍｏｌ）に４規定塩酸ジオキサン５ｍｌ、エタノール１ｍｌを加え９６時間撹拌した。溶媒を減圧留去して得られた残留物をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液１０ｍｌに溶解して２４時間撹拌した。溶媒を減圧留去して得られた残留物を６規定塩酸５ｍｌに溶解し８０℃で２時間撹拌した。溶媒を減圧留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。収量 ４６ｍｇ（０．０８ｍｍｏｌ） 収率 ６％
MS(ESI,m/z)441(MH+)
H-NMR(DMSO-d6)δ2.90(3H,br),3.00(3H,br),3.70(2H,dt),4.28(2H,t),4.23(2H,s,keto form)6.85(1H,s,enol form)7.35-7.50(4H,m),7.88(2H,d),8.33(1H,d),8.83(1H,t),9.00(2H,br),9.25(2H,Br),9.75(1H,enol,s)
実施例８１
３−［４−アミジノ−２−［２−［４−（４−ピペリジルメチル）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩の合成
工程１
２−アセチルアミノ−３−［４−シアノ−２−［２−［４−［（１−ｔ−ブトキシカルボニル−４−ピペリジル）メチル］ベンゾイルアミノ］エトキシ］フェニル］−アクリル酸メチルの合成 ４−［（１−ｔ−ブトキシカルボニルピペリジン−４−イル）メチル］安息香酸メチル６００ｍｇ（１．８０ｍｍｏｌ）に１規定水酸化ナトリウム４ｍｌ、エタノール６ｍｌを加え、１８時間撹拌した。反応液を１規定塩酸で酸性にした後、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物にジクロロメタン１０ｍｌに溶解させ、トリエチルアミン１．２５ｍｌ（９．０６ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩３７８ｍｇ（１．９８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２６７ｍｇ（１．９８ｍｍｏｌ）、３−（２−アミノエトキシ）−４−ヨードベンゾニトリル塩酸塩２０２ｍｇ（１．０２ｍｍｏｌ）を加え、２０時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をアセトニトリル１０ｍｌに溶解させ、メチル−２−アセタミドアクリラート４７８ｍｇ（３．３４ｍｍｏｌ）、酢酸パラジウム（ＩＩ）４１ｍｇ（０．１７ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン３５５ｍｇ（１．１７ｍｍｏｌ）、トリブチルアミン６１８ｍｇ（３．３４ｍｍｏｌ）を加え１８時間加熱還流した。溶媒留去後、反応液を水に希釈した後、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ５３０ｍｇ（０．８５ｍｍｏｌ） 収率 ５１％
H-NMR(CDCl3)δ1.04-1.17(2H,m),1.42(9H,s),1.58-1.77(3H,m),1.98(3H,s),2.54(2H,d),2.73-2.89(2H,m),3.78(3H,s),3.89(2H,dt),3.96-4.08(2H,m),4.31(2H,t),6.95-7.03(1H,m),7.11(2H,d),7.12-7.19(2H,m),7.23-7.27(1H,m),7.29-7.34(1H,m),7.43(1H,br),7.63(2H,d)
工程２
３−［４−アミジノ−２−［２−［４−（４−ピペリジルメチル）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩の合成
２−アセチルアミノ−３−［４−シアノ−２−［２−［４−［（１−ｔ−ブトキシカルボニル−４−ピペリジル）メチル］ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチル５３０ｍｇ（０．８５ｍｍｏｌ）を出発原料として、実施例８０の工程３と同様の操作に従って表題化合物を得た。
収量 １５０ｍｇ（０．２２ｍｍｏｌ） 収率 ２５％
MS(ESI,m/z)467(MH+)
H-NMR(DMSO-d6)δ1.23-1.40(2H,m),1.62-1.73(2H,m),1.76-1.90(1H,m),2.59(2H,d),2.72-2.91(2H,m),3.17-3.30(2H,m),3.68(2H,dt),4.21(2H,s,keto form),4.29(2H,t),6.82(1H,s,enol form),7.27(2H,d),7.34-7.49(2H,m),7.80(2H,d),8.34(1H,d),8.66-8.74(1H,m),9.12(2H,br),9.25(2H,br),9.78(1H,br,enol form)
実施例８２
３−［４−アミジノ−２−［２−［４−（ピロリジン−１−イル）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 トリフルオロ酢酸塩の合成
工程１
２−アセチルアミノ−３−［４−シアノ−２−［２−［４−（ピロリジン−１−イル）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチルの合成
４−（ピロリジン−１−イル）安息香酸４００ｍｇ（２．０９ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解させ、トリエチルアミン１．２５ｍｌ（９．０６ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩４３９ｍｇ（２．３０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール３１０ｍｇ（２．３０ｍｍｏｌ）、３−（２−アミノエトキシ）−４−ヨードベンゾニトリル塩酸塩６３６ｍｇ（２．０９ｍｍｏｌ）を加え、１９時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をアセトニトリル１５ｍｌに溶解させ、メチル−２−アセタミドアクリラート５０３ｍｇ（３．５１ｍｍｏｌ）、酢酸パラジウム（ＩＩ）４３ｍｇ（０．１８ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン３７５ｍｇ（１．２３ｍｍｏｌ）、トリブチルアミン６４９ｍｇ（３．５１ｍｍｏｌ）を加え１８時間加熱還流した。溶媒留去後、反応液を水に希釈した後、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ６５０ｍｇ（１．３７ｍｍｏｌ） 収率 ７８％
H-NMR(CDCl3)δ1.92-2.10(7H,m),3.11-3.28(3H,m),3.74-3.83(5H,m),4.24(2H,t),6.45(2H,d),6.65-6.73(1H,m),7.18(1H,d),7.24(1H,br),7.31-7.42(2H,m),7.61(2H,d)
工程２
３−［４−アミジノ−２−［２−［４−（ピロリジン−１−イル）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 トリフルオロ酢酸塩の合成
２−アセチルアミノ−３−［４−シアノ−２−［２−［４−（ピロリジン−１−イル）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチル６５０ｍｇ（１．３７ｍｍｏｌ）を実施例８０工程３と同様の操作に従って表題化合物を得た。
収量 １３０ｍｇ（０．２４ｍｍｏｌ） 収率 １７％
MS(ESI,m/z)439(MH+)
H-NMR(DMSO-d6)δ1.88-2.04(4H,m),3.23-3.35(4H,m),3.67(2H,dt),4.21(2H,s,keto form),4.23(2H,t),6.52(2H,d),6.82(1H,s,enol form),7.31-7.52(2H,m),7.72(2H,d),8.27-8.39(2H,m),9.00(2H,br),9.26(2H,br),9.78(1H,br,enol form)
実施例８３
（４Ｓ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸 二トリフルオロ酢酸塩および
（４Ｓ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩の合成
工程１
（４Ｓ）−４−ｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｌ−グルタミン酸−γ−ベンジルエステル６．７５ｇ（２０．０ｍｍｏｌ）を出発原料とし実施例５１工程１と同様の操作に従い表題化合物を得た。
収量 ６．９０ｇ（１６．３ｍｍｏｌ） 収率 ８１％
H-NMR(CDCl3)δ1.44(9H,s),1.69(2H,br),2.02(2H,br),3.98(2H,br),4.83(1H,br),5.11(2H,s),7.04-7.16(4H,m),7.24-7.40(5H,m)
工程２
（４Ｓ）−４−（４−シアノベンゾイルアミノ）−５−（３−シアノフェノキシ）ペンタン酸ベンジルの合成
（４Ｓ）−４−ｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジル６．９０ｇ（１６．３ｍｍｏｌ）を出発原料とし、実施例５１工程２と同様の操作に従い表題化合物を得た。
収量 ３．５６ｇ（７．８５ｍｍｏｌ） 収率 ４８％
H-NMR(CDCl3)δ2.10-2.28(2H,m),2,54(1H,ddd),2.69(1H,ddd),4.10(1H,dd),4.18(1H,dd),4.48(1H,br),5.12(2H,s),7.00(1H,br),7.14-7.19(2H,m),7.24-7.41(7H,m),7.72(2H,d),7.87(2H,d)
工程３
（４Ｓ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩の合成
（４Ｓ）−４−（４−シアノベンゾイルアミノ）−５−（３−シアノフェノキシ）ペンタン酸ベンジル３．５６ｇ（７．８５ｍｍｏｌ）を出発原料とし、実施例５１工程３と同様の操作に従い表題化合物を得た。
収量 ２．１９ｇ（３．３５ｍｍｏｌ） 収率 ４３％
MS(ESI,m/z)426(MH+)
H-NMR(DMSO-d6)δ1.15(3H,t),1.88-1.98(1H,m),2.01-2.11(1H,m),2.45(2H,ddd),4.03(2H,q),4.11(1H,dd),4.19(1H,dd),4.38(1H,br),7.34(1H,d),7.39(1H,d),7.40(1H,s),7.54(1H,dd),7.91(2H,d),8.05(2H,d),8.66(1H,d),9.17(2H,s),9.29(4H,s),9.42(2H,s)
工程４
（４Ｓ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸 二トリフルオロ酢酸塩の合成
（４Ｓ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩１．５７ｇ（２．４０ｍｍｏｌ）を出発原料とし、実施例５１工程４と同様の操作に従い表題化合物を得た。収量 ４２４ｍｇ（０．６７７ｍｍｏｌ） 収率 ２８％
MS(ESI,m/z)398(MH+)
H-NMR(DMSO-d6)δ1.84-1.96(1H,m),1.98-2.10(1H,m),2.37(2H,ddd),4.11(1H,dd),4.20(1H,dd),4.38(1H,br),7.33(1H,d),7.39(1H,d),7.40(1H,s),7.91(2H,d),8.05(2H,d),8.65(1H,d),9.18(2H,s),9.26(2H,s),9.29(2H,s),9.41(2H,s)
実施例８４
（４Ｒ）−４−（４−カルバモイルベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸 二トリフルオロ酢酸塩の合成
工程１
（４Ｒ）−４−ｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−グルタミン酸−γ−ベンジルエステル３．３７ｇ（１０．０ｍｍｏｌ）を出発原料とし、実施例５１工程１と同様の操作に従い表題化合物を得た。
収量 ３．２０ｇ（７．５４ｍｍｏｌ） 収率 ７５％
H-NMR(CDCl3)δ1.44(9H,s),1.69(2H,br),2.02(2H,br),3.98(2H,br),4.83(1H,br),5.11(2H,s),7.04-7.16(4H,m),7.24-7.40(5H,m)
工程２
（４Ｒ）−４−（４−シアノベンゾイルアミノ）−５−（３−シアノフェノキシ）ペンタン酸ベンジルの合成
（４Ｒ）−４−ｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジル３．２０ｇ（７．５４ｍｍｏｌ）を出発原料とし、実施例５１工程２と同様の操作に従い表題化合物を得た。
収量 ２．１６ｇ（４．７６ｍｍｏｌ） 収率 ６３％
H-NMR(CDCl3)δ2.10-2.28(2H,m),2,54(1H,ddd),2.69(1H,ddd),4.10(1H,dd),4.18(1H,dd),4.48(1H,br),5.12(2H,s),7.00(1H,br),7.14-7.19(2H,m),7.24-7.41(7H,m),7.72(2H,d),7.87(2H,d)
工程３
（４Ｒ）−４−（４−カルバモイルベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸 二トリフルオロ酢酸塩の合成
（４Ｒ）−４−（４−シアノベンゾイルアミノ）−５−（３−シアノフェノキシ）ペンタン酸ベンジルを出発原料とし、実施例６０工程２と同様の操作に従い表題化合物を得た。
MS(ESI,m/z)399(MH+)
H-NMR(DMSO-d6)δ1.90(1H,br),2.01(1H,br),2.36(2H,br),4.08(1H,dd),4.17(1H,dd),4.36(1H,br),7.35(1H,d),7.39(1H,d),7.41(1H,s),7.53(1H,t),7.92(2H,d),7.96(2H,d),8.08(2H,br),8.50(1H,d),9.14(2H,br),9.27(2H,br)
実施例８５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−（１−アセトイミドイルピペリジン−４−イル）オキシベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−ベンジル−４−（ピペリジン−４−イル）オキシベンズアミド 二トリフルオロ酢酸塩２３０ｍｇ（０．３４ｍｍｏｌ）をエタノール３ｍｌに溶解し、トリエチルアミン０．２５ｍｌ（１．７４ｍｍｏｌ）、エチル アセトイミダート塩酸塩８７ｍｇ（０．７１ｍｍｏｌ）を加え室温で６時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １９６ｍｇ（０．２６９ｍｍｏｌ） 収率 ８１％
MS(ESI,m/z)473(MH+)
H-NMR(DMSO-d6)δ1.65-1.80(2H,m),2.00-2.10(2H,m),2.31(3H,s),3.52(2H,t),3.57-3.80(3H,m),4.12-4.30(2H,m),4.60-4.80(4H,m),7.01(2H,d),7.20-7.40(10H,m),7.50(1H,t),8.62(1H,s),9.17(1H,s),9.32(4H,brs)
実施例８６
Ｎ−［（１Ｒ）−１−ベンジル−２−（３−アミジノフェノキシ）エチル］−４−（ピロリジン−１−イル）ベンズアミド 二トリフルオロ酢酸塩の合成
Ｄ−フェニルアラニンメチルエステル 塩酸塩を実施例７１工程２と同様にして（２Ｒ）−２−（ｔ−ブトキシカルボニルアミノ）−３−フェニルプロピオン酸メチルを得た。これを実施例７１工程４と同様にして（１Ｒ）−１−ベンジル−２−ヒドロキシエチルカルバミン酸ｔ−ブチルとし、実施例７１工程５、工程６と同様にして（１Ｒ）−１−ベンジル−２−（３−シアノフェノキシ）エチルカルバミン酸ｔ−ブチルを得た。この（１Ｒ）−１−ベンジル−２−（３−シアノフェノキシ）エチルカルバミン酸ｔ−ブチル１．５５ｇ（４．４０ｍｍｏｌ）を用い実施例５９と同様の操作を行い表題化合物を得た。
収量 ５６８ｍｇ（１．０２ｍｍｏｌ） 収率 ２３．２％
MS(ESI,m/z)443(MH+)
H-NMR(DMSO-d6)δ1.82-2.01(4H,m),2.92-3.10(2H,m),3.18-3.37(4H,m),4.05(1H,dd),4.19(1H,dd),4.42-4.57(1H,m),6.53(2H,d),7.15-7.42(8H,m),7.55(1H,dd),7.67(2H,d),8.08(1H,d),9.22(2H,brs),9.27(2H,brs)
実施例８７
Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−（４−ヒドロキシベンジル）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
（２Ｒ）−２−（ｔ−ブトキシカルボニル）アミノ−２−［４−（エトキシカルボニルオキシ）ベンジル］エタノールの合成
Ｄ−チロシン ３．５ｇ（１９．３ｍｍｏｌ）を出発原料とし、ジ−ｔ−ブチルジカーボネートによりｔ−ブトキシカルボニル化して（２Ｒ）−２−（ｔ−ブトキシカルボニル）アミノ−３−［４−ヒドロキシフェニル］プロピオン酸とした後、クロロ蟻酸エチル、ジイソプロピルエチルアミンを用いて混合酸無水物としたのち水素化ホウ素ナトリウムを用いて還元して表題化合物を得た。収量 ５．７２ｇ
H-NMR(CDCl3)δ1.38(3H,t),1.42(9H,s),2.83(2H,d),3.58(1H,dd),3.65(1H,dd),3.78-3.88(1H,m),4.28(2H,q),4.73(1H,d),7.11(2H,d),7.22(2H,d)
工程２
Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−（４−ヒドロキシベンジル）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１で得られた粗製物（２Ｒ）−２−（ｔ−ブトキシカルボニル）アミノ−２−［４−（エトキシカルボニルオキシ）ベンジル］エタノール５．７２ｇを用い実施例７１工程５、工程６と同様の操作を行い（１Ｒ）−１−［４−（エトキシカルボニルオキシ）ベンジル］−２−（３−シアノフェノキシ）エチルカルバミン酸ｔ−ブチルを得た。これを実施例５１工程２と同様にし続いて実施例１工程６と同様にして表題化合物を得た。
収量 １６．５ｍｇ
MS(ESI,m/z)432(MH+)
H-NMR(DMSO-d6)δ2.83(1H,dd),2.97(1H,dd),4.10-4.23(2H,m),4.43-4.57(1H,m),6.63(2H,d),7.10(2H,d),7.28(1H,dd),7.36-7.41(2H,m),7.58(1H,dd),7.90(2H,d),8.01(2H,d),8.75(1H,d),9.25(2H,s),9.31(2H,s),9.38(2H,s),9.41(2H,s)
実施例８８
Ｎ−［（１Ｒ）−１−（４−ヨードベンジル）−２−（３−アミジノフェノキシ）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩および
４−［（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−３−（３−アミジノフェノキシ）プロピル］安息香酸メチル 二トリフルオロ酢酸塩の合成
工程１
Ｄ−４−ヨードフェニルアラニンの合成
Ｄ−フェニルアラニン２０ｇ（１２１ｍｍｏｌ）、濃硫酸１４．５ｍｌ、酢酸１１０ｍｌ中によう素１２．３ｇ（４８ｍｍｏｌ）、よう素酸ナトリウム５．１ｇ（２４ｍｍｏｌ）を加え２４時間撹拌した。冷却後、過よう素酸ナトリウム０．５ｇを加え、３５℃で溶媒を減圧留去した。水を加えジクロロメタンにて２回洗浄した。水槽を１規定水酸化ナトリウムで中和し、冷却後、沈殿を濾過し水、エタノールで洗浄し、粗製物を得た。
収量 ３０ｇ（１０３ｍｍｏｌ） 収率 ８５％
工程２
（２Ｒ）−２−ｔ−ブトキシカルボニルアミノ−３−（４−ヨードフェニル）プロピオン酸メチルの合成
氷冷下、メタノール３ｍｌに塩化チオニル１７ｍｌ（２３０ｍｍｏｌ）を加えた後、Ｄ−４−ヨードフェニルアラニン２２．２ｇ（７６．３ｍｍｏｌ）を加え２時間加熱還流した。溶媒を留去して得られた残留物にＮ−メチルモルホリン１５ｍｌ（１３７ｍｍｏｌ）、ジ−ｔ−ブチルカルボネート１２ｇ（５５ｍｍｏｌ）、ジクロロメタン１００ｍｌを加え１９時間撹拌した。反応液を水で希釈し、ジクロロメタンにて抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 １２．２ｇ（３５．８ｍｍｏｌ） 収率 ４７％
H-NMR(CDCl3)δ1.42(9H,s),2.83-3.18(2H,m),3.71(3H,s),4.43-4.60(2H,m),4.84-5.06(1H,m),6.85(2H,d),7.60(2H,d)
工程３
［（１Ｒ）−２−クロロ−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチルの合成 （２Ｒ）−ｔ−ブトキシカルボニルアミノ−３−（４−ヨードフェニル）プロピオン酸メチル６．２ｇ（１８ｍｍｏｌ）にメタノール２５ｍｌ、テトラヒドロフラン２５ｍｌを加え、氷冷下、水素化ホウ素ナトリウム３．４４ｇ（９１ｍｍｏｌ）を加え１７時間撹拌した。１規定塩酸に反応液をゆっくりあけ、酢酸エチルで抽出した。有機層を水、１規定塩酸、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物にジクロロメタン５０ｍｌを加え、氷冷下、トリエチルアミン５．０２ｍｌ（３６ｍｍｏｌ）、メタンスルホニルクロライド３．０９ｇ（２７ｍｍｏｌ）を加え３０分撹拌後、室温に戻して１５時間撹拌した。反応液を水で希釈し、ジクロロメタンにて抽出した。有機層を１規定塩酸、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去して得られた残留物にジメチルホルムアミド４０ｍｌ、塩化リチウム３．８５ｇ（９１ｍｍｏｌ）を加え５０℃で１９時間撹拌した。反応液を水で希釈し、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ３．４ｇ（８．６ｍｍｏｌ） 収率 ４７％
H-NMR(CDCl3)δ1.43(9H,s),2.80-2.93(2H,m),3.48(1H,dd),3.62(1H,dd),4.00-4.18(1H,m),7.00(2H,d),7.63(2H,d)
工程４
［（１Ｒ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチルの合成
［（１Ｒ）−２−クロロ−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチル１．６ｇ（０．６０ｍｍｏｌ）、ジメチルホルムアミド２５ｍｌに、３−シアノフェノール７２４ｍｇ（６．０８ｍｍｏｌ）、炭酸カリウム１．１２ｇ（８．１ｍｍｏｌ）を加え７０℃で５５時間撹拌した。反応液を水で希釈し、酢酸エチルにて抽出した。有機層を水、飽和食塩水で順次洗浄後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。収量 １．４４ｇ（３．０１ｍｍｏｌ） 収率 ７４％
H-NMR(CDCl3)δ1.43(9H,s),2.93(2H,d),3.84-3.94(2H,m),4.73-4.89(1H,m),6.94(2H,d),7.09(2H,d),7.13(1H,d),7.38(1H,dd),7.60(2H,d)
工程５
Ｎ−［（１Ｒ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］−４−シアノベンズアミドの合成
［（１Ｒ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］カルバミン酸ｔ−ブチル１．４４ｇ（３．０１ｍｍｏｌ）を４規定塩酸ジオキサン５ｍｌ、ジオキサン２．５ｍｌに溶解させ、１５時間撹拌した。溶媒を減圧留去し残留物をジクロロメタン１０ｍｌに溶解させ、４−シアノ安息香酸４８８ｍｇ（３．３ｍｍｏｌ）、トリエチルアミン１．３ｍｌ（９．３ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩６３３ｍｇ（１．５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール４４５ｍｇ（３．３ｍｍｏｌ）を加え、１６時間撹拌した。反応液を水で希釈し、酢酸エチルで抽出した。有機層を水、１規定水酸化ナトリウム、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 １．５１ｇ（３．００ｍｍｏｌ） 収率 ９９％
H-NMR(CDCl3)δ3.03-3.17(2H,m),3.97-4.18(2H,m),4.62-4.77(1H,m),7.00(2H,d),7.18(2H,dd),7.30(1H,dd),7.41(1H,dd),7.61(2H,d),7.77(2H,d),7.83(2H,d)
工程６
Ｎ−［（１Ｒ）−１−（４−ヨードベンジル）−２−（３−アミジノフェノキシ）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩および
４−［（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−３−（３−アミジノフェノキシ）プロピル］安息香酸メチル 二トリフルオロ酢酸塩の合成
Ｎ−［（１Ｒ）−２−（３−シアノフェノキシ）−１−（４−ヨードベンジル）エチル］−４−シアノベンズアミドを出発原料とし実施例３９工程１と同様にしてカルボニル化を行った後、実施例１工程６と同様にして表題化合物を得た。
４−アミジノ−Ｎ−［（２Ｒ）−（３−アミジノフェノキシ）−１−（ヨードベンジル）エチル］ベンズアミド 二トリフルオロ酢酸塩
収量 ８ｍｇ（０．０１５ｍｍｏｌ） 収率 １％
MS(ESI,m/z)543(MH+)
H-NMR(DMSO-d6)δ2.86-3.12(2H,m),4.13-4.27(2H,m),4.48-4.62(1H,m),7.12(2H,d),7.30-7.45(3H,m),7.54(1H,dd),7.62(2H,d),7.88(2H,d),7.96(2H,d),8.78(1H,d),9.12(2H,br),9.22(2H,br),9.28(2H,br)9.39(2H,br)
４−［（２Ｒ）−（４−アミジノベンゾイルアミノ）−３−（３−アミジノフェノキシ）−２−プロピル］安息香酸メチル 二トリフルオロ酢酸塩
収量 ４７ｍｇ（０．０６７ｍｍｏｌ） 収率 ７％
MS(ESI,m/z)474(MH+)
H-NMR(DMSO-d6)δ3.02-3.25(2H,m),3.81(3H,s),4.17-4.28(2H,m),4.55-4.71(1H,m),7.32-7.50(2H,m),7.55(1H,dd),7.87(4H,dd),7.95(2H,d),8.80(1H,d),9.10(2H,br),9.20(2H,br),9.28(2H,br)9.38(2H,br)
実施例８９
Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−（３−インドリルメチル）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｄ−トリプトファンメチルエステル 塩酸塩５．０９ｇ（２０．０ｍｍｏｌ）を出発原料とし中間体を精製することなく実施例８６と同様に処理し、表題化合物を得た。ただし、４−（ピロリジン−１−イル）安息香酸の代わりに４−シアノ安息香酸を用いた。
収量 ２０９ｍｇ（０．３０６ｍｍｏｌ） 収率 １．５％
MS(ESI,m/z)455(MH+)
H-NMR(DMSO-d6)δ3.02-3.12(2H,m),4.20-4.35(2H,m),4.60-4.88(2H,m),6.95-7.66(13H,m),7.85(2H,d),8.03(2H,d),8.81(1H,d),9.07-9.41(8H,m),10.81(1H,s)
実施例９０
４−［（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−３−（３−アミジノフェノキシ）プロピル］安息香酸 二トリフルオロ酢酸塩の合成
４−［（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−３−（３−アミジノフェノキシ）プロピル］安息香酸メチル 二トリフルオロ酢酸塩８ｍｇ（０．０１１ｍｍｏｌ）に濃塩酸を５ｍｌ加え、６０℃で１９時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ６ｍｇ（０．００９ｍｍｏｌ） 収率 ８０％
MS(FAB,m/z)460(MH+)
H-NMR(DMSO-d6)δ3.00-3.24(2H,m),4.46-4.26(2H,m),4.58-4.68(1H,m),7.33-7.48(2H,m),7.55(1H,dd),7.84(2H,d),7.87(2H,d),7.94(2H,d),8.79(1H,d),9.08(2H,br),9.18(2H,br),9.28(2H,br)9.37(2H,br)
実施例９１
（２Ｓ）−２−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸 二トリフルオロ酢酸塩の合成
工程１
（２Ｓ）−２−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｌ−アスパラギン酸−α−ベンジルエステル３．２３ｇ（１０．０ｍｍｏｌ）、トリエチルアミン１．３９ｍｌ（１０．０ｍｍｏｌ）をテトラヒドロフラン５０ｍｌに溶解し、氷冷下クロロギ酸エチル０．９６ｍｌ（１０．０ｍｍｏｌ）を加え２０分間撹拌した。生じた析出物を吸引濾過により除去し、濾液に氷３ｇ、水素化ホウ素ナトリウム３８０ｍｇ（１０．０ｍｍｏｌ）を氷冷下加え１．５時間撹拌した。ここに１規定塩化水素水溶液を５０ｍｌを加え室温で更に１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた油状残渣をテトラヒドロフラン３０ｍｌに溶解し、３−シアノフェノール７３７ｍｇ（６．１８ｍｍｏｌ）、トリフェニルホスフィン１．７７ｇ（６．７４ｍｍｏｌ）、アゾジカルボン酸ジエチル（４０％トルエン溶液）２．７０ｇ（６．１８ｍｍｏｌ）を加え室温で一晩撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 １．１２ｇ（２．７３ｍｍｏｌ） 収率 ２７％
H-NMR(CDCl3)δ1.40(9H,s),2.30(2H,br),4.05(2H,t),4.58(1H,br),5.20(2H,t),5.70(1H,br),7.0-7.2(4H,m),7.3(5H,s)
工程２
（２Ｓ）−２−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成
（２Ｓ）−２−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブタン酸ベンジル１．１２ｇ（２．７３ｍｍｏｌ）を４規定塩化水素のジオキサン溶液１０ｍｌに溶解し、室温で２時間撹拌した。溶媒を留去し得られた油状残渣をジクロロメタン１４ｍｌに溶解し、氷冷下４−シアノ安息香酸３９０ｍｇ（２．７３ｍｍｏｌ）、ＨＯＢｔ４０５ｍｇ（３．００ｍｍｏｌ）、トリエチルアミン０．８３ｍｌ（６．００ｍｍｏｌ）、ＷＳＣ．ＨＣｌ５７５ｍｇ（３．００ｍｍｏｌ）を順次加え、室温で一晩撹拌した。塩化メチレンを抽出溶媒とし常法に従って処理し、表題化合物を得た。
収量 ９００ｍｇ（２．０５ｍｍｏｌ） 収率 ７５％
H-NMR(CDCl3)δ2.50(2H,br),4.10(2H,t),5.05(1H,q),5.20(1H,d),5.28(1H,d),6.9-7.3(4H,m),7.36(5H,s),7.72(2H,d),7.89(2H,d)
工程３
（２Ｓ）−２−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸 二トリフルオロ酢酸塩の合成
（２Ｓ）−２−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブタン酸ベンジル９００ｍｇ（２．０５ｍｍｏｌ）を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール２０ｍｌに加え、室温で一晩撹拌した。続いて溶媒を減圧下留去した後、室温でアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液２０ｍｌに溶解して室温で一晩撹拌した。溶媒を留去して得られた残留物を濃塩酸１０ｍｌに溶解し４０℃で４時間撹拌した。塩化水素を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ３６４ｍｇ（０．５９６ｍｍｏｌ） 収率 ２９％
MS(ESI,m/z)384(MH+)
H-NMR(DMSO-d6)δ2.20(2H,br),4.20(2H,br),4.70(1H,br),7.30(1H,d),7.38(1H,br),7.93(2H,d),8.08(2H,d),9.02(1H,d),9.20(2H,s),9.30(2H,s),9.34(2H,s),9.47(2H,d).
実施例９２
（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸 二トリフルオロ酢酸塩の合成
工程１
（２Ｒ）−２−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−アスパラギン酸−α−ベンジルエステル５．０ｇ（１５．０ｍｍｏｌ）を出発原料とし実施例９１の合成、工程１と同様にして表題化合物を得た。
収量 ３．１３ｇ（７．６３ｍｍｏｌ） 収率 ５１％
H-NMR(CDCl3)δ1.40(9H,s),2.30(2H,br),4.05(2H,t),4.58(1H,br),5.20(2H,t),5.70(1H,br),7.0-7.2(4H,m),7.3(5H,s)
工程２
（２Ｒ）−２−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成
（２Ｒ）−２−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブタン酸ベンジル３．１３ｇ（７．６３ｍｍｏｌ）を出発原料とし実施例９１の合成、工程２と同様にして表題化合物を得た。
収量 ２．１９ｇ（６．６２ｍｍｏｌ） 収率 ８７％
H-NMR(CDCl3)δ2.50(2H,br),4.10(2H,t),5.05(1H,q),5.20(1H,d),5.28(1H,d),6.9-7.3(4H,m),7.36(5H,s),7.72(2H,d),7.89(2H,d)
工程３
（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸 二トリフルオロ酢酸塩の合成
（２Ｒ）−２−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブタン酸ベンジル２．９１ｇ（６．６２ｍｍｏｌ）をを出発原料とし実施例９１の合成、工程３と同様にして表題化合物を得た。
収量 ８９５ｍｇ（１．４６ｍｍｏｌ） 収率 ２２％
MS(ESI,m/z)384(MH+)
H-NMR(DMSO-d6)δ2.20(2H,br),4.20(2H,br),4.70(1H,br),7.30(1H,d),7.38(1H,br),7.93(2H,d),8.08(2H,d),9.02(1H,d),9.20(2H,s),9.30(2H,s),9.34(2H,s),9.47(2H,d).
実施例９３
活性化血液凝固第Ｘ因子阻害活性の測定
評価化合物の水溶液１０μｌにｐＨ８．４に調製した１００ｍＭトリス−塩酸緩衝液１３０μｌを加え、次いでヒト活性化血液凝固第Ｘ因子（エンザイム リサーチ（Enzyme Research）社製）をｐＨ８．４トリス−塩酸緩衝液で０．５ユニット／ｍｌに調製した溶液１０μｌを加え、室温で１０分間インキュベートした。次いで、Ｎ−ベンゾイル−Ｌ−イソロイシル−Ｌ−グルタミル−グリシル−Ｌ−アルギニル−Ｐ−ニトロアニリド塩酸塩（（株）ペプチド研究所製）をｐＨ８．４トリス−塩酸緩衝液で０．８ｍＭに調製した溶液５０μｌを加え、吸光度を測定し、反応初速度を求めた。評価化合物の溶液の代わりにｐＨ８．４に調製したトリス−塩酸緩衝液１０μｌを加えたものをコントロールとした。吸光度の測定はマイクロプレート リーダー モデル 3550-UV（MICROPLATE READER Model 3550-UV）（バイオ ラッド（BIO RAD)社製）を用い、４０５ｎｍの波長で１５秒間隔で１６分間測定した。評価化合物無添加の時の活性化血液凝固第Ｘ因子の活性（初速度）を５０％阻害するときの評価化合物の濃度の負の対数値を求め（ｐＩＣ５０と略す）、活性化血液凝固第Ｘ因子阻害活性の指標とした。代表的な化合物の活性化血液凝固第Ｘ因子阻害活性を下記表−１に示す。
実施例９４
トロンビン阻害活性の測定
評価化合物の水溶液１０μｌにｐＨ８．４に調製した１００ｍＭトリス−塩酸緩衝液１３０μｌを加え、次いでヒトのトロンビン（シグマ（SIGMA）社製）をｐＨ８．４トリス−塩酸緩衝液で２ユニット／ｍｌに調製した溶液１０μｌを加え、室温で１０分間インキュベートした。次いで、Ｄ−フェニルアラニル−Ｌ−ピペコリル−Ｌ−アルギニル−Ｐ−ニトロアニリド二塩酸塩（第一化学薬品社製、Ｓ−２２３８）をｐＨ８．４トリス−塩酸緩衝液で０．４ｍＭに調製した溶液５０μｌを加え、吸光度を測定し、反応初速度を求めた。評価化合物の溶液の代わりにｐＨ８．４に調製したトリス−塩酸緩衝液１０μｌを加えたものをコントロールとした。吸光度の測定はマイクロプレート リーダー モデル 3550-UV（MICROPLATE READER Model 3550-UV）（バイオ ラッド（BIO RAD）社製）を用い、４０５ｎｍの波長で１５秒間隔で１６分間測定した。評価化合物無添加の時のトロンビンの活性（初速度）を５０％阻害するときの評価化合物の濃度の負の対数値を求め（ｐＩＣ５０と略す）、トロンビン阻害活性の指標とした。代表的な化合物のトロンビン阻害活性を下記表−１に示す。
Figure 0004103147
ただし表中、実施例８３の化合物は（４Ｓ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸 二トリフルオロ酢酸塩を示す。
この結果より本発明のベンズアミジン誘導体は、活性化血液凝固第Ｘ因子に特異的な高い阻害活性を示すことがわかる。
以下、実施例で述べた本発明化合物の構造式を示す。
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
実施例９５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
実施例１の工程１〜４によりＮ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミドを合成した。
工程５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミド２．４３ｇ（８．３５ｍｍｏｌ）を４規定塩化水素のジオキサン溶液５６ｍｌに溶解したものに塩化水素を３０％含有する（Ｗ／Ｖ）エタノール２４ｍｌを加えた。室温で９６時間撹拌した後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液３０ｍｌに溶解して室温で２４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １．１９ｇ（２．１５ｍｍｏｌ） 収率 ２６％
MS(FAB,m/z)326(MH+)
H-NMR(DMSO-d6)δ3.69(2H,dt),4.24(2H,t),7.32(1H,d),7.39(1H,d),7.40(1H,s),7.53(1H,t),7.90(2H,d),8.05(2H,d),9.02(1H,t),9.18(2H,br),9.30(4H,br),9.43(2H,br)
実施例９６
Ｎ−［２−（３−アミジノフェノキシ）エチル］−３−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−３−シアノベンズアミドの合成
３−シアノ安息香酸１６２ｍｇ（１．１ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル１６３ｍｇ（１．０ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
収量 ２５１ｍｇ（０．８６ｍｍｏｌ） 収率 ８６％
H-NMR(CDCl3)δ3.92(2H,dt),4.19(2H,t),6.67(1H,br),7.16(1H,d),7.18(1H,s),7.28(1H,d),7.40(1H,t),7.59(1H,t),7.80(1H,t),7.80(1H,d),8.03(1H,d),8.09(1H,s)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−３−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−３−シアノベンズアミド２４０ｍｇ（０．８２ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 ６６．３ｍｇ（０．１２ｍｍｏｌ） 収率 １４％
MS(FAB,m/z)326(MH+)
H-NMR(DMSO-d6)δ3.70(2H,dt),4.25(2H,t),7.32(1H,d),7.41(1H,d),7.45(1H,s),7.51(1H,t),7.71(1H,t),7.97(1H,d),8.18(1H,d),8.45(1H,s),8.92(4H,br),9.14(1H,t)
実施例９７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（４−ピペリジルオキシ）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸エチルの合成
４−ヒドロキシ安息香酸エチル１．７ｇ（１０．２ｍｍｏｌ）、１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン１．７６ｇ（９．３ｍｍｏｌ）、トリフェニルホスフィン２．４４ｇ（９．３ｍｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解し、アゾジカルボン酸ジエチル１．６２ｇ（９．３ｍｍｏｌ）を室温で加え一晩撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．５７ｇ（４．５ｍｍｏｌ） 収率 ４４％
H-NMR(CDCl3)δ1.38(3H,t),1.50(9H,s)1.70-1.80(2H,m),1.90-2.00(2H,m),3.30-3.41(2H,m),3.63-3.75(2H,m),4.35(2H,q),4.55(1H,m),6.90(2H,d),8.00(2H,d)
工程２
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸の合成
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸エチル８４７ｍｇ（２．４３ｍｍｏｌ）をエタノール５０ｍｌに溶解し、１規定水酸化ナトリウム溶液を５ｍｌを加え３日間室温で撹拌した。反応液を濃縮し、酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し表題化合物を得た。
収量 ６９７ｍｇ （２．２ｍｍｏｌ） 収率 ９２％
H-NMR(CDCl3)δ1.50(9H,s),1.70-2.00(4H,m),3.30-3.40(2H,m),3.65-3.75(2H,m),4.60(1H,s),6.95(2H,d),8.05(2H,d)
工程３
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンズアミドの合成
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸２１１．２ｍｇ（０．６５ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル 塩酸塩１２９．２ｍｇ（０．６５ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
収量 １６７ｍｇ（０．３６ｍｍｏｌ） 収率 ５５％
H-NMR(CDCl3)δ1.50(9H,s),1.65-1.80(2H,m),1.85-2.00(2H,m),3.30-3.40.(2H,m),3.60-3.75(2H,m),3.90(2H,dt),4.20(2H,t),4.55(1H,m),6.45(1H,t),6.94(2H,d),7.15(1H,d),7.17(1H,s),7.26(1H,d),7.38(1H,t),6.74(2H,d)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（４−ピペリジルオキシ）ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）ベンズアミド１６５ｍｇ（０．３５ｍｍｏｌ）を出発原料とし実施例１の工程３と同様の操作によりＮ−［２−（３−シアノフェノキシ）エチル］−４−（４−ピペリジルオキシ）ベンズアミドへと変換した後、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 １２４ｍｇ（０．２０ｍｍｏｌ） 収率 ５７％
MS(ESI,m/z)383(MH+)
H-NMR(DMSO-d6)δ1.80-1.90(2H,m),2.08-2.18(2H,m),3.02-3.30(4H,m),3.62(2H,q),4.21(2H,t),4.75(1H,m),7.06(2H,d),7.30-7.42(3H,m),7.53(1H,t),7.85(2H,d),8.58(2H,br),8.61(1H,br),9.12(2H,br),9.28(2H,br)
実施例９８
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（アミノメチル）ベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（アミノメチル）安息香酸エチルの合成
４−アミノメチル安息香酸 ３ｇ（１９．９ｍｍｏｌ）をエタノール１００ｍｌに懸濁し、２５％塩化水素を含むエタノール１０ｍｌを加え8時間加熱環流した。溶媒を留去し、酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し表題化合物を得た。
収量 １．１９ｇ（６．７７ｍｍｏｌ） 収率 ３４％
H-NMR(CDCl3)δ1.35(3H,t),4.05(2H,brs),4.30(2H,q),6.60(2H,d),7.85(2H,d)
工程２
４−［（ｔ−ブトキシカルボニルアミノ）メチル］安息香酸エチルの合成
４−（アミノメチル）安息香酸エチル、ジ−ｔ−ブチルジカルボネートを出発原料とし、実施例１の工程１と同様の操作により表題化合物を得た。
H-NMR(CDCl3)δ1.45(9H,s),4.36(2H,d),4.36(2H,q),4.90(1H,br),7.35(2H,d),8.00(2H,d)
工程３
４−［（ｔ−ブトキシカルボニルアミノ）メチル］安息香酸の合成
４−［（ｔ−ブトキシカルボニルアミノ）メチル］安息香酸エチルを出発原料とし、実施例９７の工程２と同様の操作により表題化合物を得た。
H-NMR(CDCl3)δ1.43(9H,s),4.40(2H,br),4.95(1H,br),7.40(2H,d),8.10(2H,d)
工程４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（アミノメチル）ベンズアミド 二トリフルオロ酢酸塩の合成
４−［（ｔ−ブトキシカルボニルアミノ）メチル］安息香酸４３９ｍｇ（２ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル 塩酸塩４００ｍｇ（２ｍｍｏｌ）を出発原料とし実施例１の工程４と同様の操作によりＮ−［２−（３−シアノフェノキシ）エチル］−４−［（ｔ−ブトキシカルボニルアミノ）メチル］ベンズアミドとした。このものを実施例１の工程３と同様の操作に従いＮ−［２−（３−シアノフェノキシ）エチル］−４−（アミノメチル）ベンズアミド 塩酸塩へと変換した後、実施例９５の工程５と同様の操作により表題化合物を得た。
MS(ESI,m/z)313(MH+)
H-NMR(DMSO-d6)δ3.70(2H,q),4.10(2H,s),4.25(2H,t),7.30-7.40(3H,m),7.51-7.56(3H,m),7.91(2H,d),8.24(3H,br),8.78(1H,t),9.10(2H,br),9.27(2H,br)
実施例９９
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（１−アセトイミドイル−４−ピペリジルオキシ）ベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（４−ピペリジルオキシ）ベンズアミド 二トリフルオロ酢酸塩１２４ｍｇ（０．２ｍｍｏｌ）をエタノール５ｍｌに溶解し、トリエチルアミン１８３ｍｇ（１．８ｍｍｏｌ）、エチルアセトイミダート 塩酸塩１４７ｍｇ（１．２ｍｍｏｌ）を加え室温で６日間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １２０ｍｇ（０．１８ｍｍｏｌ） 収率 ９２％
MS(ESI,m/z)424(MH+)
H-NMR(DMSO-d6)δ1.70-1.82(2H,m),2.02-2.14(2H,m),2.30(3H,s),3.50-3.60(2H,m),3.65(2H,q),3.70-3.80(2H,m),4.20(2H,t),4.80(1H,m),7.07(2H,d),7.30-7.40(3H,m),7.53(1H,t)7.85(2H,d)8.57-8.63(2H,m),9.11-9.18(3H,m),9.28(2H,br)
実施例１００
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（Ｅ）−３−（４−アミジノフェニル）−２−プロペンアミド 二トリフルオロ酢酸塩の合成
工程１
（Ｅ）−３−（４−シアノフェニル）アクリル酸の合成
４−ブロモベンゾニトリル３．６４ｇ（２０ｍｍｏｌ）、アクリル酸２．８８ｇ（４０ｍｍｏｌ）をアセトニトリル４０ｍｌに溶解し、酢酸パラジウム（ＩＩ）４９ｍｇ（０．２ｍｍｏｌ）、トリ−ｏ−トリルホスフィン３６５ｍｇ（１．２ｍｍｏｌ）、トリブチルアミン７．４１ｇ（４０ｍｍｏｌ）を加え一晩加熱環流した。反応液を４規定塩化水素に注ぎ生じる沈殿を濾取し、４規定塩化水素、水、酢酸エチルで洗浄後、真空乾燥し表題化合物を得た。
収量 ２．３６ｇ（１３．６ｍｍｏｌ） 収率 ６８％
H-NMR(DMSO-d6)δ6.70(1H,d),7.65(1H,d),7.90(4H,m)
工程２
Ｎ−［２−（３−シアノフェノキシ）エチル］−（Ｅ）−３−（４−シアノフェニル）−２−プロペンアミドの合成
（Ｅ）−３−（４−シアノフェニル）アクリル酸１７３ｍｇ（１ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル１４６ｍｇ（０．９ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
収量 ２５４ｍｇ（０．８ｍｍｏｌ） 収率 ８９％
H-NMR(CDCl3)δ3.82(2H,q),4.15(2H,t),6.10(1H,br),6.50(1H,d),7.15(1H,d),7.18(1H,s),7.25(1H,d),7.40(1H,t),7.60(2H,d),7.68(1H,d),7.70(2H,d)
工程３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（Ｅ）−３−（４−アミジノフェニル）−２−プロペンアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−（Ｅ）−３−（４−シアノフェニル）−２−プロペンアミド２５４ｍｇ（０．８ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 ２３ｍｇ（０．０４ｍｍｏｌ） 収率 ５％
MS(ESI,m/z)326(MH+)
H-NMR(DMSO-d6)δ3.60(2H,q),4.20(2H,t),6.85(1H,d),7.34(1H,d),7.38(1H,s),7.40(1H,d),7.54(1H,d),7.55(1H,t),7.79(2H,d),7.85(2H,d),8.54(1H,br),9.18(4H,br),9.28(2H,br),9.33(2H,br)
実施例１０１
Ｎ−［３−（３−アミジノフェノキシ）エチル］−４−［（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル］ベンズアミド トリフルオロ酢酸塩の合成
工程１
４−（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル安息香酸メチルの合成
４−（ｔ−ブトキシカルボニルアミノ）メチル安息香酸３６５ｍｇ（１．４５ｍｍｏｌ）、水素化ナトリウム（油性、６０％）１６０ｍｇ（４ｍｍｏｌ）をジメチルホルムアミドに溶解し、室温で５分間撹拌後ヨウ化メチル１ｍｌを加えさらに２時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ３８０ｍｇ（１．３６ｍｍｏｌ） 収率 ９４％
工程２
４−（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル安息香酸の合成
４−（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル安息香酸メチル３７０ｍｇ（１．３ｍｍｏｌ）を出発原料とし、実施例９７の工程２と同様の操作により表題化合物を得た。
収量 ３３０ｍｇ（１．２４ｍｍｏｌ） 収率 ９５％
工程３
Ｎ−［３−（３−アミジノフェノキシ）エチル］−４−［（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル］ベンズアミド トリフルオロ酢酸塩の合成
４−（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル安息香酸３３０ｍｇ（１．２４ｍｍｏｌ）、３−（２−アミノエトキシ）ベンズアミジン二塩酸塩３１３ｍｇ（１．２４ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様に、縮合及び逆相高速液体クロマトグラフィーによる精製を行い表題化合物を得た。
収量 １５５ｍｇ（０．２３７ｍｍｏｌ） 収率 ２０％
MS(ESI,m/z)427(MH+)
実施例１０２
Ｎ−［３−（３−アミジノフェノキシ）エチル］−４−［（メチルアミノ）メチル］ベンズアミド 二トリフルオロ酢酸塩 の合成
Ｎ−［３−（３−アミジノフェノキシ）エチル］−４−［（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル］ベンズアミド トリフルオロ酢酸塩１４０ｍｇ（０．２６ｍｍｏｌ）をトリフルオロ酢酸に溶解し、室温で３０分間撹拌した。続いて、トリフルオロ酢酸を留去して表題化合物を得た。
収量 １３３ｍｇ（０．２４ｍｍｏｌ） 収率 ９２％
MS(ESI,m/z)411(MH+ +DMSO-d6)
実施例１０３
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［１−ｔ−ブトキシカルボニル−（３Ｓ）−３−ピロリジルオキシ］フェニルアセトアミド トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−１−（ｔ−ブトキシカルボニル）−３−ヒドロキシ−ピロリジンの合成
ｔｒａｎｓ−４−ヒドロキシ−Ｌ−プロリン２５．０ｇ（１９１ｍｍｏｌ）、シクロヘキサノン１．５ｍｌをシクロヘキサノール１５０ｍｌに溶解し、１６０℃で１６時間撹拌した。メチルイソブチルケトンで希釈し、１規定塩酸水溶液を抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。こうして得られた油状残渣をテトラヒドロフラン３００ｍｌ、水３００ｍｌに溶解し０℃でトリエチルアミン３４ｍｌ（２４４ｍｍｏｌ）、ジ−ｔ−ブチルジカーボネート３１．４ｇ（１４３ｍｍｏｌ）を加え、４時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２７．４ｇ（１４６ｍｍｏｌ） 収率 ７６％
MS(FAB,m/z)188(MH+)
H-NMR(CDCl3)δ1.46(9H,s),2.25-2.31(2H,m)3.20-3.57(4H,m),4.42(1H,s),4.74(1H,s)
工程２
２−［４−［（３Ｓ）−１−（ｔ−ブトキシカルボニル）−３−ピロリジルオキシ］フェニル］酢酸エチルの合成
４−ヒドロキシフェニル酢酸エチル６．０ｇ（３３．３ｍｍｏｌ）、（３Ｒ）−１−（ｔ−ブトキシカルボニル）−３−ヒドロキシ−ピロリジン６．２５ｇ（３３．３ｍｍｏｌ）、トリフェニルフォスフィン１０．５ｇ（４０ｍｍｏｌ）をテトラヒドロフラン１２５ｍｌに溶解しアゾジカルボン酸ジエチル６．３ｍｌ（４０ｍｍｏｌ）を室温で加え、４２時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ５．７ｇ（１６．３ｍｍｏｌ） 収率 ４９％
MS(FAB,m/z)349(MH+)
H-NMR(CDCl3)δ1.24(3H,t),1.46(9H,s),2.05-2.20(2H,m),3.50(2H,s),3.40-3.62(4H,m),4.15(2H,q),4.85(1H,s),6.81(1H,d),6.83(1H,d),7.19(1H,d),7.23(1H,d)
工程３
２−［４−［（３Ｓ）−１−ｔ−ブトキシカルボニル−３−ピロリジルオキシ］フェニル］酢酸の合成
２−［４−［（３Ｓ）−１−（ｔ−ブトキシカルボニル）−３−ピロリジルオキシ］フェニル］酢酸エチル７５０ｍｇをエタノール１０ｍｌに溶解し、１規定水酸化ナトリウム水溶液４ｍｌを加えた。室温で一晩撹拌した後、溶媒を留去した。１規定塩酸を加え、酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し表題化合物を得た。
収量 ８３０ｍｇ
H-NMR(CDCl3)δ1.45(9H,s),2.00-2.20(2H,m),3.42-3.62(6H,m),3.85(1H,brs),6.80(2H,d),7.20(2H,d)
工程４
４−［１−ｔ−ブトキシカルボニル−（３Ｓ）−３−ピロリジルオキシ］フェニル酢酸の合成
４−［１−ｔ−ブトキシカルボニル−（３Ｓ）−３−ピロリジルオキシ］フェニル酢酸エチルを出発原料とし、実施例９７の工程２と同様の操作により表題化合物を得た。
工程５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［１−ｔ−ブトキシカルボニル−（３Ｓ）−３−ピロリジルオキシ］フェニルアセトアミド トリフルオロ酢酸塩の合成
４−［１−ｔ−ブトキシカルボニル−（３Ｓ）−３−ピロリジルオキシ］フェニル酢酸、３−（２−アミノエトキシ）ベンズアミジン 二塩酸塩を出発原料とし、実施例１２４の工程５と同様に縮合反応及び逆相高速液体クロマトグラフィーによる精製を行い表題化合物を得た。
MS(ESI,m/z)483(MH+)
H-NMR(DMSO-d6)δ1.40(9H,s),1.95-2.15(2H,m),3.25-3.55(8H,m),4.10(2H,t),4.90(1H,brs),6.84(2H,d),7.17(2H,d),7.30(1H,d),7.36(1H,s),7.38(1H,d),7.53(1H,t),8.26(1H,brt),9.04(2H,brs),9.28(2H,brs)
実施例１０４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（３Ｓ）−３−ピロリジルオキシ］フェニルアセトアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［１−ｔ−ブトキシカルボニル−（３Ｓ）−３−ピロリジルオキシ］フェニルアセトアミドトリフルオロ酢酸塩を４規定塩化水素のジオキサン溶液に溶解し、室温で１時間撹拌した。溶媒を留去後、得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
MS(ESI,m/z)383(MH+)
H-NMR(DMSO-d6)δ2.05-2.25(2H,m),3.20-3.60(8H,m),4.10(2H,t),7.08(2H,d),7.20(2H,d),7.30(1H,d),7.40(1H,d),7.38(1H,s),7.54(1H,t),8.36(1H,brt),9.19(2H,brs),9.31(2H,brs),9.33(2H,brs)
実施例１０５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（１−アセチル−４−ピペリジン）カルボアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−（１−アセチル−４−ピペリジン）カルボアミドの合成
１−アセチル−４−ピペリジンカルボン酸１７５ｍｇ（１．０２ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル１５０ｍｇ（０．９２ｍｍｏｌを出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
収量 ８４．４ｍｇ（０．２７ｍｍｏｌ） 収率 ２９％
H-NMR(CDCl3)δ1.60-1.77(2H,m),1.82-1.93(2H,m),2.10(3H,s),2.35(1H,m),2.65(1H,m),3.09(1H,m),3.69(2H,dt),3.87(1H,m),4.06(2H,t),4.60(1H,m),5.97(1H,br),7.12(1H,d),7.14(1H,s),7.27(1H,d),7.40(m,t)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（１−アセチル−４−ピペリジン）カルボアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−（１−アセチル−４−ピペリジン）カルボアミド７５ｍｇ（０．２４ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 １２．３ｍｇ（０．０２８ｍｍｏｌ） 収率 １２％
MS(ESI,m/z)333(MH+)
H-NMR(CD3OD)δ1.43-1.82(4H,m),2.15(3H,s),2.50(1H,m),2.65(1H,m),3.15(1H,m),3.60(2H),3.95(1H,m),4.15(2H,t),4.50(1H,m),7.31(1H,d),7.35(1H,s),7.37(1H,d)7.52(1H,t)
実施例１０６ Ｎ−［２−（３−アミジノフェノキシ）エチル］−（１Ｓ）−１０−カンファースルホンアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−（１Ｓ）−１０−カンファースルホンアミドの合成
３−（２−アミノエトキシ）ベンゾニトリル７００ｍｇ（４．３２ｍｍｏｌ）をＤＭＦ２０ｍｌに溶解し、ジイソプロピルエチルアミン０．７５ｍｌ（４．３２ｍｍｏｌ）、およびＤＭＦ５ｍｌに溶解した（１Ｓ）−（＋）−１０−カンファースルホニルクロリド１．０８ｇ（４．３２ｍｍｏｌ）を０℃で加え、４時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量１．４１ｇ（３．７５ｍｍｏｌ） 収率 ８７％
MS(ESI,m/z)377(MH+)
H-NMR(CDCl3)δ0.88(3H,s),1.04(3H,s),1.47(1H,ddd),1.89-2.15(5H,m),2.33(1H,td),2.98(1H,d),3.46(1H,d),3.59(2H,dt),4.14(2H,t),6.00(1H,t),7.15(1H,d),7.18(1H,s),7.26(1H,d),7.39(1H,t)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（１Ｓ）−１０−カンファースルホンアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−（１Ｓ）−１０−カンファースルホンアミド１．４１ｇ（３．７５ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作に従い表題化合物を得た。
収量 ３４２ｍｇ（０．６７ｍｍｏｌ） 収率 １８％
MS(ESI,m/z)394(MH+)
H-NMR(DMSO-d6)δ0.86(3H,s),0.93(3H,s),1,38(1H,ddd),1.78-1.91(2H,m),2.17-2.21(2H,m),2.52(1H,d),2.56(1H,d),3.05-3.30(2H,m),4.00-4.05(2H,m),4.37(2H,t),7.34(1H,d),7.40(1H,s),7.45(1H,d),7.55(1H,q),9.13(2H,s),9.31(2H,s)
実施例１０７
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（１Ｒ）−１０−カンファースルホンアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−（１Ｒ）−１０−カンファースルホンアミドの合成
３−（２−アミノエトキシ）ベンゾニトリル７００ｍｇ（４．３２ｍｍｏｌ）、（１Ｒ）−（−）−１０−カンファースルホニルクロリド１．０８ｇ（４．３２ｍｍｏｌ）を出発原料とし、実施例１０６の工程１と同様の操作に従い表題化合物を得た。
収量 １．３３ｇ（３．５４ｍｍｏｌ） 収率 ８２％
MS(ESI,m/z)377(MH+)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（１Ｒ）−１０−カンファースルホンアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−（１Ｒ）−１０−カンファースルホンアミド１．３３ｇ（３．５４ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作に従い表題化合物を得た。
収量 ３２０ｍｇ（０．６３ｍｍｏｌ） 収率 １８％
MS(ESI,m/z)394(MH+)
H-NMR(DMSO-d6)δ0.86(3H,s),0.93(3H,s),1,35(1H,ddd),1.78-1.91(2H,m),2.12-2.21(2H,m),2.59(1H,d),2.76(1H,d),3.11(1H,d),3.14(1H,d),4.08(2H,br),4.37(2H,br),7.33(1H,dd),7.40(1H,s),7.42(1H,d),7.56(1H,t),7.55(1H,q),9.11(2H,s),9.31(2H,s)
実施例１０８
１−［２−（３−アミジノフェノキシ）エチルカルバモイル］メチル］キヌクリジニウム 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］ブロモアセトアミドの合成
３−（２−アミノエトキシ）ベンゾニトリル１．５０ｇ（９．２６ｍｍｏｌ）、ジイソプロピルエチルアミン１．７７ｍｌ（１０．２ｍｍｏｌ）をテトラヒドロフラン１５ｍｌに溶解し、テトラヒドロフラン５ｍｌに溶解したブロモアセチルクロリド０．９２ｍｌ（１１．１ｍｍｏｌ）を０℃で加え８時間撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ２．１８ｇ（７．７３ｍｍｏｌ） 収率 ８３％
MS(ESI,m/z)305(M+Na+)
H-NMR(CDCl3)δ3.76(2H,dt),3.98(2H,d),4.08(2H,t),7.14(1H,dd),7.16(1H,s),7.28(1H,dd),7.39(1H,td)
工程２
［１−［２−（３−アミジノフェノキシ）エチルカルバモイル］メチル］キヌクリジニウム二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］ブロモアセトアミド５００ｍｇ（１．７７ｍｍｏｌ）、キヌクリジン１９６ｍｇ（１．７７ｍｍｏｌ）をクロロホルム５ｍｌに溶解し、１００℃で２時間、さらに室温で１５時間撹拌した後、溶媒を留去し油状残渣を得た。こうして得られた油状残渣を実施例９５の工程５と同様の操作に従って処理し表題化合物を得た。
収量 ２５８ｍｇ（０．４６ｍｍｏｌ） 収率 ２６％
MS(ESI,m/z)331(M+)
H-NMR(DMSO-d6)δ1.88(6H,m),2.07(1H,br),3.58(8H,m),3.95(2H,s),4.14(2H,t),7.29(1H,dd),7.39(1H,s),7.43(1H,d),7.53(1H,t),9.02(1H,t),9.34(2H,s),9.55(2H,s)
実施例１０９
Ｎ−［２−（３−アミジノフェノキシ）エチル］−（３−キヌクリジニル）アミノアセトアミド 三トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−ブロモアセトアミド５００ｍｇ（１．７７ｍｍｏｌ）、３−アミノキヌクリジン塩酸塩４２３ｍｇ（２．１３ｍｍｏｌ）、炭酸カリウム５８６ｍｇ（４．２５ｍｍｏｌ）、ヨウ化カリウム３２３ｍｇ（１．９５ｍｍｏｌ）をＤＭＦ５ｍｌに溶解し、０℃で１０５分、さらに室温で６時間撹拌した。溶媒を減圧留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、結晶性物質を得た。こうして得られた結晶性物質を実施例９５の工程５と同様の操作に従って処理し表題化合物を得た。
収量 ８０ｍｇ（０．１２ｍｍｏｌ） 収率 ６．８％
MS(ESI,m/z)346(MH+)
H-NMR(DMSO-d6)δ1.91-2.03(4H,m),2.28-2.38(1H,m),3.10-3.40(5H,m),3.55(2H,dd),3.70-3.83(2H,m),4.08(2H,t),4,15(2H,m),7.27(1H,s),7.32(1H,d),7.46(1H,d),7.54(1H,t),9.23(2H,br),9.46(2H,br)
実施例１１０
３−［２−（２−ナフタレンスルフォニルアミノ）エトキシ］ベンズアミジン トリフルオロ酢酸塩の合成
工程１
３−［２−（２−ナフタレンスルフォニルアミノ）エトキシ］ベンゾニトリルの合成
３−（２−アミノエトキシ）ベンゾニトリル１６３ｍｇ、ジイソプロピルエチルアミン０．５ｍｌをジメチルホルムアミド１０ｍｌに溶解し、氷冷下ジメチルホルムアミドに溶解した２−ナフタレンスルホニルクロリド２５０ｍｇ（１．１ｍｍｏｌ）を加え、氷冷下２時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により表題化合物を得た。
収量 ３２０ｍｇ（０．９１ｍｍｏｌ） 収率 ９１％
H-NMR(CDCl3)δ3.45(2H,dt),4.00(2H,t),5.05(1H,br),6.96(1H,s),6.97(1H,d),7.20(1H,d),7.30(1H,t),7.59-7.70(2H,m),7.82-7.98(4H,m),8.46(1H,s)
工程２
３−［２−（２−ナフタレンスルフォニルアミノ）エトキシ］ベンズアミジン トリフルオロ酢酸塩の合成
３−［２−（２−ナフタレンスルフォニルアミノ）エトキシ］ベンゾニトリル３００ｍｇ（０．８５ｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 １６８ｍｇ（０．３５ｍｍｏｌ） 収率 ４１％
MS(FAB,m/z)384(MH+)
H-NMR(DMSO-d6)δ3.20(2H,br),4.10(2H,br),7.14(1H,d),7.22(1H,s),7.33(1H,d),7.44(1H,t),7.60-8.20(7H,m),8.41(1H,s),9.10(4H,br)
実施例１１１
３−［２−（４−アミジノベンゼンスルフォニルアミノ）エトキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
工程１
３−［２−（４−ブロモベンゼンスルフォニルアミノ）エトキシ］ベンゾニトリルの合成
４−ブロモベンゼンスルホニルクロリド４６０ｍｇ（１．８ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル２９４ｍｇ（１．８ｍｍｏｌ）を出発原料とし、実施例１１０の工程１と同様の操作により表題化合物を得た。
収量 ６０４ｍｇ（１．７ｍｍｏｌ） 収率 ９４％
H-NMR(CDCl3)δ3.40(2H,dt),4.02(2H,t),5.00(1H,br),7.03(1H,d),7.50(1H,s),7.27(1H,d),7.37(1H,t),7.65(2H,d),7.75(2H,d)
工程２
３−［２−（４−シアノベンゼンスルフォニルアミノ）エトキシ］ベンゾニトリルの合成
３−［２−（４−ブロモベンゼンスルフォニルアミノ）エトキシ］ベンゾニトリル３００ｍｇ（０．８４ｍｍｏｌ）をＮ−メチルピロリドン１ｍｌに溶解し、シアン化銅（Ｉ）７６ｍｇ（０．８４ｍｍｏｌ）を加え１４０℃で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ４５ｍｇ（０．１４ｍｍｏｌ） 収率 １６％
MS(ESI,m/z)350(MNa+)
H-NMR(CDCl3)δ3.25(2H,dt),4.05(2H,t),5.15(1H,br),7.40(1H,d),7.50(1H,s),7.28(1H,d),7.38(1H,t),7.82(2H,d),8.01(2H,d)
また同時に、４−［２−（３−シアノフェノキシ）エチルスルファモイル］ベンズアミドを得た。
収量 ２１ｍｇ（０．０６ｍｍｏｌ） 収率 ７％
H-NMR(CD3OD)δ3.35(2H,t),4.00(2H,t),7.10(1H,d),7.15(1H,s),7.39(1H,t),7.92-8.01(4H,m)
工程３
３−［２−（４−アミジノベンゼンスルフォニルアミノ）エトキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［２−（４−シアノベンゼンスルフォニルアミノ）エトキシ］ベンゾニトリル４０ｍｇ（０．１４ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 ９．０ｍｇ（０．０１５ｍｍｏｌ） 収率 １１％
MS(ESI,m/z)362(MH+)
H-NMR(DMSO-d6)δ3.20(2H,dt),4.10(2H,t),7.21(1H,d),7.33(1H,s),7.40(1H,d),7.51(1H,t),7.98-8.05(4H,m),8.41(1H,br)9.25(2H,br),9.30(2H,br),9.48(4H,br)
実施例１１２
４−［２−（３−アミジノフェノキシ）エチルスルファモイル］ベンズアミド トリフルオロ酢酸塩の合成
４−［２−（３−シアノフェノキシ）エチルスルファモイル］ベンズアミド２０ｍｇ（０．０５８ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 ５ｍｇ（０．０１０ｍｍｏｌ） 収率 １７％
MS(ESI,m/z)363(MH+)
H-NMR(DMSO-d6)δ3.20(2H,dt),4.05(2H,q),7.20(1H,d),7.31(1H,s),7.37(1H,d),7.50(1H,t),7.59(1H,br),7.89(2H,d),8.02(2H,d),8.10(1H,br),8.14(1H,br),9.05(2H,br),9.30(2H,br)
実施例１１３
３−［２−（４−ブロモベンゼンスルフォニルアミノ）エトキシ］ベンズアミジン トリフルオロ酢酸塩の合成
３−［２−（４−ブロモベンゼンスルフォニルアミノ）エトキシ］ベンゾニトリル４０ｍｇ（０．１１ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 ２６ｍｇ（０．０４ｍｍｏｌ） 収率 ３６％
MS(ESI,m/z)398(MH+),400((M+2)H+)
H-NMR(DMSO-d6)δ3.20(2H,dt),4.05(2H,t),7.20(1H,d),7.28(1H,s),7.38(1H,d),7.51(1H,t),7.73-7.82(4H,m),8.10(1H,br),9.10(2H,br),9.28(2H,br)
実施例１１４
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−フェニルメチル−４−アミジノベンズアミド二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−Ｎ−フェニルメチル−４−シアノベンズアミドの合成
水素化ナトリウム（油性６０％）２８ｍｇ（０．７ｍｍｏｌ）をジメチルホルムアミド中氷冷下撹拌した。Ｎ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミド２００ｍｇ（０．６９ｍｍｏｌ）を少量のジメチルホルムアミドに溶解して加えた。水素の発生が終わった後にベンジルブロミド２５７ｍｇ（１．５ｍｍｏｌ）を加えた後、室温で２時間撹拌した。溶媒を減圧留去した後に１Ｎ塩化水素を加え酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により表題化合物を得た。
収量 ３１５ｍｇ（０．８３ｍｍｏｌ） 収率 ＞１００％
H-NMR(CDCl3)アミドの回転異性体Ａ、Ｂの１：３混合物δ3.30(2H,brs,A),3.85(2H,brs,B),3.85(2H,brs,A),4.25(2H,brs,B),4.61(2H,brs,B),4.85(2H,brs,A),6.90-7.75(13H,m)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−フェニルメチル−４−アミジノベンズアミド 二トリフルオロ酢酸塩
Ｎ−［２−（３−シアノフェノキシ）エチル］−Ｎ−フェニルメチル−４−シアノベンズアミド３００ｍｇ（０．７９ｍｍｏｌ）を用いて実施例９５の工程５と同様の操作により表題化合物を得た。
収量 １５２ｍｇ（０。２４ｍｍｏｌ） 収率 ３０％
MS(ESI,m/z)416(MH+)
H-NMR(DMSO-d6)アミドの回転異性体Ａ、Ｂの１：１混合物δ3.55(2H,brs,A or B),3.75(2H,brs,A or B),4.10(2H,brs,A or B),4.30(2H,brs,A or B),4.60(2H,brs,A or B),4.80(2H,brs,A or B),7.20-7.95(13H,m),9.20-9.50(8H,m)
実施例１１５
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−メチル−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（３−シアノフェノキシ）エチル］−Ｎ−メチル−４−シアノベンズアミドの合成 Ｎ−［２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミド２００ｍｇ（０．６９ｍｍｏｌ）、ヨウ化メチル５００ｍｇ（過剰量）を出発原料とし実施例１１４の工程１と同様の操作により表題化合物を得た。
収量 ２２１ｍｇ（０．７３ｍｍｏｌ） 収率 ＞１００％
H-NMR(CDCl3)アミドの回転異性体Ａ、Ｂの１：３混合物δ3.15(3H,brs,B),3.20(3H,brs,A),3.70(2H,brs,A),3.95(2H,brs,B),4.05(2H,brs,A),4.30(2H,brs,B),7.04-7.20(2H,m),7.28(1H,d),7.40(1H,t),7.49-7.59(2H,m),7.72(2H,d)
工程２
Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−メチル−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−Ｎ−メチル−４−シアノベンズアミド２００ｍｇ（０．６６ｍｍｏｌ）を出発原料とし実施例９５の工程５と同様の操作により表題化合物を得た。
収量 １３０ｍｇ（０．２３ｍｍｏｌ） 収率 ３５％
MS(ESI,m/z):340(MH+)
H-NMR(DMSO-d6)アミドの回転異性体Ａ、Ｂの１：１混合物δ3.00(3H,s,A or B),3.05(3H,s,A or B),3.62(2H,s,A or B),3.90(2H,s,A or B),4.15(2H,s,A or B),4.35(2H,s,A or B),7.22-7.70(6H,m),7.90(2H,d),9.18-9.42(8H,m)
実施例１１６
Ｎ−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−ベンジルエチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［（１Ｓ）−１−ベンジル−２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミドの合成
Ｌ−フェニルアラニンメチルエステル 塩酸塩 ４．５ｇ（２０．９ｍｍｏｌ）を出発原料とし中間体を精製することなく実施例１１７工程１と同様の操作を行い粗製物を得た。シリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．０３ｇ（２．７０ｍｍｏｌ） 収率 １２．９％
MS(ESI,m/z)489(MH+)
H-NMR(CDCl3)δ3.15(2H,d),4.01-4.18(2H,m),4.63-4.80(1H,m),6.67(1H,d),7.15-7.42(9H,m),7.67(2H,d),7.81(2H,d)
工程２
Ｎ−［（１Ｓ）−２−（３−アミジノフェノキシ）−１−ベンジルエチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［（１Ｓ）−１−ベンジル−２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミド１．０３ｇ（２．７０ｍｍｏｌ）を用い実施例１１７工程２と同様操作を行い表題化合物を得た。
収量 ３０５ｍｇ（０．４７４ｍｍｏｌ） 収率 １７．６％
MS(ESI,m/z)416(MH+)
H-NMR(DMSO-d6)δ2.95-3.17(2H,m),4.12-4.27(2H,m),4.55-4.62(1H,m),7.17-7.85(2H,d),7.97(2H,d),8.80(1H,d),9.24(2H,br),9.30(2H,br),9.42(4H,br)
実施例１１７
Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−ベンジルエチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［（１Ｒ）−１−ベンジル−２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミドの合成
Ｄ−フェニルアラニンメチルエステル 塩酸塩 ４．５ｇ（２０．９ｍｍｏｌ）を出発原料とし中間体を精製することなく実施例１５０の工程２、４、５、６、実施例１の工程３、４と同様の操作を順次行い粗製物を得た。シリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ０．９５ｇ（２．４９ｍｍｏｌ） 収率 １１．９％
MS(ESI,m/z)(MH+)
H-NMR(CDCl3)δ3.17(2H,d),4.01-4.17(2H,m),4.67-4.80(1H,m),6.38(1H,d),7.08-7.42(9H,m),7.75(2H,d),7.82(2H,d)
工程２
Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−ベンジルエチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［（１Ｒ）−１−ベンジル−２−（３−シアノフェノキシ）エチル］−４−シアノベンズアミド０．９５ｇ（２．４９ｍｍｏｌ）を用い実施例１５０の工程７と同様操作を行い表題化合物を得た。
収量 １８８ｍｇ（０．４７４ｍｍｏｌ） 収率 １７．６％
MS(ESI,m/z)416(MH+)
H-NMR(DMSO-d6)δ2.95-3.18(2H,m),4.17-4.27(2H,m),4.52-4.62(1H,m),7.19-7.57(9H,m),7.85(2H,d),7.98(2H,d),8.79(1H,d),9.24(2H,br),9.32(2H,br),9.42(4H,br)
実施例１１８
（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸エチル 二トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−アスパラギン酸−β−ベンジルエステル３．２３ｇ（１０．０ｍｍｏｌ）、トリエチルアミン１．３９ｍｌ（１０．０ｍｍｏｌ）をテトラヒドロフラン５０ｍｌに溶解し、氷冷下クロロギ酸エチル０．９６ｍｌ（１０．０ｍｍｏｌ）を加え２０分間撹拌した。生じた析出物を吸引濾過により除去し、濾液に氷５ｇ、水素化ホウ素ナトリウム０．７６ｇ（２０．０ｍｍｏｌ）を氷冷下加え１．５時間撹拌した。ここに１規定塩化水素水溶液を２０ｍｌを加え室温で更に１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた油状残渣をテトラヒドロフラン３６ｍｌに溶解し、３−シアノフェノール０．９６ｇ（８．０４ｍｍｏｌ）、トリフェニルホスフィン２．３０ｇ（８．７７ｍｍｏｌ）、アゾジカルボン酸ジエチル（４０％トルエン溶液）３．５０ｇ（８．０４ｍｍｏｌ）を加え室温で一晩撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．８０ｇ（４．３８ｍｍｏｌ） 収率 ４４％
H-NMR(CDCl3)δ1.46(9H,s),2.79(2H,d),4.00(1H,dd),4.06(1H,dd),4.41(1H,br),5.13(2H,s),5.56(1H,br),7.05-7.18(4H,m),7.21-7.38(5H,m)
工程２
（３Ｒ）−３−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブタン酸ベンジル１．８ｇ（４．３８ｍｍｏｌ）を４規定塩化水素のジオキサン溶液２０ｍｌに溶解し、０℃で６時間撹拌した。溶媒を留去し得られた油状残渣をジクロロメタン５ｍｌに溶解し、氷冷下４−シアノ安息香酸クロリド１．０９ｇ（６．５８ｍｍｏｌ）、トリエチルアミン１．２２ｍｌ（８．７６ｍｍｏｌ）を加え、室温で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．２１ｇ（２．７５ｍｍｏｌ） 収率 ６３％
H-NMR(CDCl3)δ2.86(1H,dd),2.95(1H,dd),4.12(1H,dd),4.20(1H,dd),4.85(1H,br),5.16(2H,s),7.09(1H,d),7.11(1H,dd),7.24-7.40(7H,m),7.72(2H,d),7.83(2H,d)
工程３
（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸エチル 二トリフルオロ酢酸塩の合成
（３Ｒ）−３−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブタン酸ベンジル１．２１ｇ（２．７５ｍｍｏｌ）を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール２０ｍｌに加え、室温で一晩撹拌した。続いて室温でアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液３０ｍｌに溶解して室温で二晩撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ０．４５６ｍｇ（０．７１３ｍｍｏｌ） 収率 ２５．９％
MS(ESI,m/z)412(MH+)
H-NMR(DMSO-d6)δ1.15(3H,t),2.82(2H,d),4.07(2H,q),4.12(1H,dd),4.24(1H,dd),4.72(1H,br),7.33(1H,d),7.39(1H,s),7.40(1H,d),7.54(1H,dd),7.91(2H,d),8.02(2H,d),8.84(1H,d),9.16(2H,s),9.28(4H,s),9.42(2H,s)
実施例１１９
（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸 二トリフルオロ酢酸塩の合成
（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸エチル 二トリフルオロ酢酸塩０．４６６ｇ（０．７２９ｍｍｏｌ）を濃塩酸１０ｍｌに溶解し４０℃で６時間撹拌した。塩化水素を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ０．１５１ｍｇ（０．２４７ｍｍｏｌ） 収率 ４６％
MS(ESI,m/z)384(MH+)
H-NMR(DMSO-d6)δ2.74(2H,d),4.13(1H,dd),4.24(1H,dd),4.69(1H,ddt),7.35(1H,d),7.40(1H,d),7.41(1H,s),7.55(1H,dd),7.91(2H,d),8.03(2H,d),8.81(1H,d),9.20(2H,s),9.28(2H,s),9.33(2H,s),9.43(2H,s)
実施例１２０
（４Ｒ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩の合成
工程１
（４Ｒ）−４−ｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−グルタミン酸−γ−ベンジルエステル３．３７ｇ（１０．０ｍｍｏｌ）を出発原料とし（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成と同様の操作に従い表題化合物を得た。
収量 ３．２０ｇ（７．５４ｍｍｏｌ） 収率 ７５．４％
H-NMR(CDCl3)δ1.44(9H,s),1.69(2H,br),2.02(2H,br),3.98(2H,br),4.83(1H,br),5.11(2H,s),7.04-7.16(4H,m),7.24-7.40(5H,m)
工程２
（４Ｒ）−４−（４−シアノベンゾイルアミノ）−５−（３−シアノフェノキシ）ペンタン酸ベンジルの合成
（４Ｒ）−４−ｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジル３．２０ｇ（７．５４ｍｍｏｌ）を出発原料とし、（３Ｒ）−３−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブタン酸ベンジルの合成と同様の操作に従い表題化合物を得た。
収量 ２．１６ｇ（４．７６ｍｍｏｌ） 収率 ６３．２％
H-NMR(CDCl3)δ2.10-2.28(2H,m),2,54(1H,ddd),2.69(1H,ddd),4.10(1H,dd),4.18(1H,dd),4.48(1H,br),5.12(2H,s),7.00(1H,br),7.14-7.19(2H,m),7.24-7.41(7H,m),7.72(2H,d),7.87(2H,d)
工程３
（４Ｒ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩の合成
（４Ｒ）−４−（４−シアノベンゾイルアミノ）−５−（３−シアノフェノキシ）ペンタン酸ベンジル２．１６ｇ（４．７６ｍｍｏｌ）を出発原料とし、（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸エチル 二トリフルオロ酢酸塩の合成と同様の操作に従い表題化合物を得た。
収量 １．７８ｇ（２．７２ｍｍｏｌ） 収率 ５７．２％
MS(ESI,m/z)426(MH+)
H-NMR(DMSO-d6)δ1.15(3H,t),1.88-1.98(1H,m),2.01-2.11(1H,m),2.45(2H,ddd),4.03(2H,q),4.11(1H,dd),4.19(1H,dd),4.38(1H,br),7.34(1H,d),7.39(1H,d),7.40(1H,s),7.54(1H,dd),7.91(2H,d),8.05(2H,d),8.66(1H,d),9.17(2H,s),9.29(4H,s),9.42(2H,s)
実施例１２１
（４Ｒ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸 二トリフルオロ酢酸塩の合成
（４Ｒ）−４−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩１．０２ｇ（１．５６ｍｍｏｌ）を出発原料とし、（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸 二トリフルオロ酢酸塩の合成と同様の操作に従い表題化合物を得た。
収量 ２６１ｍｇ（０．４１７ｍｍｏｌ） 収率 ２６．７％
MS(ESI,m/z)398(MH+)
H-NMR(DMSO-d6)δ1.84-1.96(1H,m),1.98-2.10(1H,m),2.37(2H,ddd),4.11(1H,dd),4.20(1H,dd),4.38(1H,br),7.33(1H,d),7.39(1H,d),7.40(1H,s),7.91(2H,d),8.05(2H,d),8.65(1H,d),9.18(2H,s),9.26(2H,s),9.29(2H,s),9.41(2H,s)
実施例１２２
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
４−［３−（３−アミジノフェノキシ）プロピルカルバモイル安息香酸エチルトリフルオロ酢酸塩の合成
工程１
Ｎ−（３−ブロモプロピル）−ｔ−ブチルカルバマートの合成
３−ブロモプロピルアミン 臭化水素酸塩１８．４ｇ（８４．２ｍｍｏｌ）、ジ−ｔ−ブチルジカルボネート１３．１ｇ（６０．０ｍｍｏｌ）を出発原料とし、実施例１の工程１と同様の操作により表題化合物を得た。
収量 １１．８ｇ（５０．０ｍｍｏｌ） 収率 ８３％
H-NMR(CDCl3)δ1.42(9H,s),2.05(2H,tt),3.25(2H,dt),3.45(2H,t)4.70(1H,br)
工程２
３−［３−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリルの合成
Ｎ−（３−ブロモプロピル）−ｔ−ブチルカルバマート６ｇ（２５．２ｍｍｏｌ）、３−ヒドロキシベンゾニトリル２ｇ（１６．８ｍｍｏｌ）を出発原料とし、実施例１の工程２と同様の操作により表題化合物を得た。
収量 ４．５１ｇ（１６．３ｍｍｏｌ） 収率 ９６％
H-NMR(CDCl3)δ1.42(9H,s),2.00(2H,tt),3.35(2H,dt),4.05(2H,t),4.70(1H,br),7.12(1H,d),7.14(1H,s),7.24(1H,d),7.37(1H,t)
工程３
３−（３−アミノプロポキシ）ベンゾニトリル 塩酸塩の合成
３−［３−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル１ｇ（３．６ｍｍｏｌ）を出発原料とし、実施例１の工程３と同様の操作により表題化合物を得た。
収量 ７５８ｍｇ（３．６ｍｍｏｌ） 収率 １００％
工程４
Ｎ−［３−（３−シアノフェノキシ）プロピル］−４−シアノベンズアミドの合成
３−（３−アミノプロポキシ）ベンゾニトリル 塩酸塩１００ｍｇ（０．４７ｍｍｏｌ）、４−シアノ安息香酸７７ｍｇ（０．５２ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
収量 １２４ｍｇ（０．４１ｍｍｏｌ） 収率 ８７％
H-NMR(CDCl3)δ2.18(2H,tt),3.70(2H,dt),4.15(2H,t),6.50(1H,br),7.15(1H,d),7.18(1H,s),7.25(1H,d),7.38(1H,t),7.75(2H,d),7.85(2H,d)
工程５
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
４−［３−（３−アミジノフェノキシ）プロピルカルバモイル］安息香酸エチル トリフルオロ酢酸塩の合成
Ｎ−［３−（３−シアノフェノキシ）プロピル］−４−シアノベンズアミド１２５ｍｇ（０．４１ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩：
収量 ３ｍｇ（０．０１ｍｍｏｌ） 収率 ２％
MS(ESI,m/z)340(MH+)
H-NMR(DMSO-d6)δ2.05(2H,tt),3.50(2H,dt),4.18(2H,t),7.31(1H,d),7.38(1H,s),7.39(1H,d),7.54(1H,s),7.89(2H,d),8.04(2H,d),8.80(1H,br),9.10(2H,br),9.20(2H,br),9.30(2H,br),9.40(2H,br)
４−［３−（３−アミジノフェノキシ）プロピルカルバモイル安息香酸エチル トリフルオロ酢酸塩：
MS(ESI,m/z)370(MH+)
H-NMR(DMSO-d6)δ1.35(3H,t),2.05(2H,tt),3.45(2H,dt),4.15(2H,t),4.35(2H,q),7.32(1H,d),7.38(1H,d),7.37(2H,s),7.55(1H,t),7.97(2H,d),8.04(2H,d),8.75(1H,br),9.05(2H,br),9.27(2H,br)
実施例１２３
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（１−アセチル−４−ピペリジン）カルボアミド トリフルオロ酢酸塩の合成
工程１
Ｎ−［３−（３−シアノフェノキシ）プロピル］−（１−アセチル−４−ピペリジン）カルボアミドの合成
（１−アセチル−４−ピペリジン）カルボン酸８９ｍｇ（０．５２ｍｍｏｌ）、３−（３−アミノプロポキシ）ベンゾニトリル 塩酸塩１００ｍｇ（０．４７ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
収量 ９８ｍｇ（０．３０ｍｍｏｌ） 収率 ６４％
H-NMR(CDCl3)δ1.50-1.90(4H,m),2.05(2H,tt),2.30(1H,m),2.65(1H,m),3.10(1H,m),3.45(2H,dt),3.85(1H,m),4.05(2H,t),4.60(1H,m),5.75(1H,br),7.15(1H,d),7.15(1H,s),7.25(1H,d),7.40(1H,t)
工程２
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（１−アセチル−４−ピペリジンカルボアミド トリフルオロ酢酸塩の合成
Ｎ−［３−（３−シアノフェノキシ）プロピル］−（１−アセチル−４−ピペリジンカルボアミド９８ｍｇ（０．３０ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 ７２ｍｇ（０．１６ｍｍｏｌ） 収率 ５３％
MS(ESI,m/z)347(MH+)
H-NMR(DMSO-d6)δ1.30-1.50(2H,m),1.70(2H,m),1.85(2H,tt),2.35(1H,m),2.55(1H,m),3.00(1H,m),3.20(2H,dt),3.80(1H,m),4.05(2H,t),4.35(1H,m),7.28(1H,d),7.35(1H,s),7.37(1H,s),7.55(1H,t),7.90(1H,br),9.20(2H,br),9.30(2H,br)
実施例１２４
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−ピペリジンカルボアミド 二トリフルオロ酢酸塩の合成
工程１
３−ヒドロキシベンズアミジン 塩酸塩の合成
３−ヒドロキシベンゾニトリル５ｇ（４２ｍｍｏｌ）を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール５０ｍｌに溶解し、室温で一晩撹拌した。溶媒を留去し得られた残渣をアンモニアを３０％含有する（Ｗ／Ｖ）エタノール溶液５０ｍｌに溶解して室温で一晩撹拌した後、溶媒を留去し表題化合物を得た。
収量 ４．４ｇ（２５．５ｍｍｏｌ） 収率 ６１％
工程２
Ｎ−ｔ−ブトキシカルボニル−３−ヒドロキシベンズアミジンの合成
３−ヒドロキシベンズアミジン 塩酸塩１ｇ（５．８ｍｍｏｌ）、ジ-ｔ-ブチルジカルボネート１．２７ｇ（５．８ｍｍｏｌ）、４-（ジメチルアミノ）ピリジン２４ｍｇ（０．２ｍｍｏｌ）、トリエチルアミン１．３０ｇ（１２．８ｍｍｏｌ）をジメチルホルムアミド２０ｍｌに溶解し、室温で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。収量 ４５８ｍｇ（１．９４ｍｍｏｌ） 収率 ３３％
H-NMR(DMSO-d6)δ1.45(9H,s),6.95(1H,d),7.25(1H,t),7.35(1H,d),7.38(1H,s),8.90(2H,br),9.65(1H,br)
工程３
Ｎ−ｔ−ブトキシカルボニル−３−［３−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンズアミジン の合成
Ｎ−ｔ−ブトキシカルボニル−３−ヒドロキシベンズアミジン、Ｎ−（３−ブロモプロピル）−ｔ−ブチルカルバマートを出発原料とし実施例１の工程２と同様の操作により表題化合物を得た。H-NMR(CDCl3)δ1.42(9H,s),1.55(9H,s),3.52(2H,dt),4.05(2H,t),4.95(1H,br),7.03(1H,d),7.33(1H,t),7.41(1H,br),7.47(1H,br)
工程４
３−（３−アミノプロポキシ）ベンズアミジン二塩酸塩の合成
３−［３−（ｔ−ブトキシカルボニルアミノ）プロポキシ］−Ｎ−ｔ−ブトキシカルボニルベンズアミジンを出発原料とし実施例１の工程３と同様の操作により表題化合物を得た。
H-NMR(DMSO-d6)δ3.20(2H,br),4.30(2H,br),7.34(1H,d),7.49(1H,d),7.51(1H,s),7.56(1H,t),8.38(3H,br),9.29(2H,br),9.50(2H,br)
工程５
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−ピペリジンカルボアミド 二トリフルオロ酢酸塩の合成
（１−ｔ−ブトキシカルボニル-４-ピペリジン）カルボン酸３０ｍｇ（０．１３ｍｍｏｌ）、Ｎ−メチルモルホリン１２ｍｇ（０．１２ｍｍｏｌ）をジメチルホルムアミド５ｍｌに溶解し、氷冷下クロロギ酸エチルを１３ｍｇ（０．１２ｍｍｏｌ）加え、５分後３-［（３-アミノプロピル）オキシ］ベンズアミジン 二トリフルオロ酢酸塩５０ｍｇ（０．１２ｍｍｏｌ）及びＮ−メチルモルホリン２４ｍｇ（０．２４ｍｍｏｌ）をジメチルホルムアミド５ｍｌに溶解したものを加え、室温で４時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。このものを４規定塩化水素のジオキサン溶液１０ｍｌに溶解し室温で２時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ：３２ｍｇ（０．０６ｍｍｏｌ） 収率 ５０％
MS(ESI,m/z)305(MH+)
H-NMR(DMSO-d6)δ1.62-1.95(6H,m),2.40(1H,m),2.90(2H,m),3.20-3.38(4H,m),4.10(2H,t),7.28(1H,d),7.38(1H,s),7.39(1H,d),7.53(1H,t),8.04(1H,br),8.46(1H,br),8.78(1H,br),9.30(2H,br),9.42(2H,br)
実施例１２５
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−アミノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
４−（ｔ−ブトキシカルボニルアミノ）安息香酸エチルの合成
４−アミノ安息香酸エチル、ジ−ｔ−ブチルジカルボネートを出発原料とし、実施例１の工程１と同様の操作により表題化合物を得た。
H-NMR(CDCl3)δ1.38(3H,t),1.55(9H,s),4.35(2H,q),6.65(1H,br),7.42(2H,d),7.95(2H,d)
工程２
４−（ｔ−ブトキシカルボニルアミノ）安息香酸の合成
４−（ｔ−ブトキシカルボニルアミノ）安息香酸エチルを出発原料とし、実施例９７の工程２と同様の操作により表題化合物を得た。
工程３
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−アミノベンズアミド 二トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二トリフルオロ酢酸塩５０ｍｇ（０．１２６ｍｍｏｌ）、４−（ｔ−ブトキシカルボニルアミノ）安息香酸４-［t-ブトキシカルボニルアミノ］安息香酸３０ｍｇ（０．１２６ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物を得た。
収量 ９．５ｍｇ（０．０１８ｍｍｏｌ） 収率 １５％
MS(ESI,m/z)313(MH+)
H-NMR(DMSO-d6)δ1.95(2H,tt),3.35(2H,dt),4.10(2H,t),6.57(2H,d),7.30(1H,d),7.36(1H,s),7.37(1H,d),7.53(1H,t)7.58(2H,d),8.08(1H,br),9.10(2H,br),9.30(2H,br)
実施例１２６
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−４−（アミノメチル）ベンズアミド二トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二トリフルオロ酢酸塩８０ｍｇ（０．１９ｍｍｏｌ）、４−（ｔ−ブトキシカルボニルアミノ）メチル安息香酸４８ｍｇ（０．１９ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物を得た。
収量 ２５ｍｇ（０．０４５ｍｍｏｌ） 収率 ２４％
MS(ESI,m/z)327(MH+)
H-NMR(DMSO-d6)δ2.00(2H,tt),3.40(2H),4.02-4.18(4H,m),7.29(1H,d),7.36-7.40(2H,m),7.48-7.54(3H,m),7.88(2H,d),8.38(3H,br),8.60(1H,br),9.30(2H,br),9.42(2H,br)
実施例１２７
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−３−アミジノベンズアミド二トリフルオロ酢酸塩の合成
３−［３−（３−アミジノフェノキシ）プロピルカルバモイル］安息香酸エチル トリフルオロ酢酸塩の合成
工程１
Ｎ−［３−（３−シアノフェノキシ）プロピル］−３−シアノベンズアミドの合成
３−シアノ安息香酸、３−（３−アミノプロポキシ）ベンゾニトリル 塩酸塩を出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
工程２
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−３−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
３−［３−（３−アミジノフェノキシ）プロピルカルバモイル］安息香酸エチル トリフルオロ酢酸塩の合成
Ｎ−［３−（３−シアノフェノキシ）プロピル］−３−シアノベンズアミド１２５ｍｇ（０．４１ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−３−アミジノベンズアミド 二トリフルオロ酢酸塩：
収量 ３ｍｇ（０．００５ｍｍｏｌ） 収率 １％
MS(ESI,m/z)340(MH+)
H-NMR(DMSO-d6)δ2.05(2H,tt),3.50(2H,dt),4.20(2H,t),7.31(1H,d),7.38(1H,s),7.39(1H,d),7.54(1H,t),7.72(1H,t),7.94(1H,d),8.18(1H,d)8.26(1H,s),8.75(1H,br),9.11(2H,br),9.21(2H,br),9.27(2H,br),9.38(2H,br)
３−［３−（３−アミジノフェノキシ）プロピルカルバモイル］安息香酸エチル トリフルオロ酢酸塩：
MS(ESI,m/z)370(MH+)
H-NMR(DMSO-d6)δ1.35(3H,t),2.05(2H,tt),3.50(2H,dt),4.15(2H,t),4.35(2H,q),7.32(1H,d),7.38(1H,s),7.39(1H,d),7.54(1H,t),7.63(1H,t),8.09(1H,d),8.13(1H,d),8.44(1H,s),8.78(1H,br),9.15(2H,br),9.28(2H,br)
実施例１２８
３−［３−（２−ナフタレンスルフォニルアミノ）プロポキシ］ベンズアミジントリフルオロ酢酸塩の合成
工程１
３−［３−（２−ナフタレンスルフォニルアミノ）プロポキシ］ベンゾニトリルの合成
２−ナフタレンスルホニルクロリド、３−（３−アミノプロポキシ）ベンゾニトリルを出発原料とし、実施例１１０の工程１と同様の操作により表題化合物を得た。
H-NMR(CDCl3)δ2.00(2H,tt),3.25(2H,dt),3.95(2H,t),4.80(1H,br),6.95(1H,s),7.00(1H,d),7.20(1H,d),7.30(1H,t),7.55-7.70(2H,m),7.80-8.00(4H,m),8.42(1H,s)
工程２
３−［３−（２−ナフタレンスルフォニルアミノ）プロポキシ］ベンズアミジントリフルオロ酢酸塩の合成
３−［３−（２−ナフタレンスルフォニルアミノ）プロポキシ］ベンゾニトリル３００ｍｇ（０．８２ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。
収量 １６９ｍｇ（０．３４ｍｍｏｌ） 収率 ４１％
MS(FAB,m/z)384(MH+)
H-NMR(DMSO-d6)δ1.85(2H,tt),3.00(2H,dt),4.00(2H,t),7.17(1H,d),7.25(1H,s),7.35(1H,d),7.45(1H,t),7.62-8.16(7H,m),8.43(1H,s),9.18(2H,br),9.24(2H,br)
実施例１２９
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｒ）−２−（ベンジルオキシカルボニルアミノ）プロピオンアミド トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩３０ｍｇ（０．１１ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニル−Ｄ−アラニン２５．８ｍｇ（０．１３５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール２３．０ｍｇ（０．１７ｍｍｏｌ）、１-エチル-３-（３-ジメチルアミノプロピル）カルボジイミド 塩酸塩２５．９ｍｇ（０．１３５ｍｍｏｌ）、Ｎ−メチルモルホリン２３ｍｇ（０．２３ｍｍｏｌ）をジメチルホルムアミド２ｍｌに溶解し、一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いて、得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ５ｍｇ（０．０１ｍｍｏｌ） 収率 ７％
MS(ESI,m/z)399(MH+)
H-NMR(DMSO-d6)δ1.20(3H,d),1.90(2H,tt),3.25(2H,dt),3.92-4.10(3H,m),5.00(2H,m),7.26-7.44(8H,m),7.53(1H,t),7.97(1H,br),9.10(2H,br),9.30(2H,br)
実施例１３０
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）プロピオンアミド トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩３．０ｍｇ（０．１１ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニル−Ｌ−アラニン２６ｍｇ（０．１３５ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物を得た。
収量 １７ｍｇ（０．０３ｍｍｏｌ） 収率 ２２％
MS(ESI,m/z)399(MH+)
H-NMR(DMSO-d6)δ1.20(3H,d),1.90(2H,tt),3.25(2H,dt),3.92-4.10(3H,m),5.00(2H,m),7.26-7.44(8H,m),7.53(1H,t),7.97(1H,br),9.10(2H,br),9.30(2H,br)
実施例１３１
（４Ｓ）−４−［３−（３−アミジノフェノキシ）プロピル］カルバモイル−４−（ベンジルオキシカルボニルアミノ）ブタン酸 トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩３０ｍｇ（０．１１ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニル−Ｌ−グルタミン酸−γ−ｔ−ブチルエステル４６ｍｇ（０．１３５ｍｍｏｌ）を出発原料とし、実施例１２９の工程１と同様の操作により表題化合物のｔ−ブチルエステルを得た。続いてこのものを４規定塩化水素のジオキサン溶液に溶解し、５時間撹拌した。溶媒を留去し、得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １２ｍｇ（０．０２ｍｍｏｌ） 収率 １５％
MS(ESI,m/z)457(MH+)
H-NMR(DMSO-d6)δ1.70-1.95(4H,m),2.25(2H,t),3.23(2H,dt),3.85-4.05(3H,m),4.95-5.05(2H,m),7.27-7.38(7H,m),7.44(1H,d),7.52(1H,t),8.02(1H,t),9.00(2H,br),9.30(2H,br)
実施例１３２
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−イミダゾリル）プロパンアミド二トリフルオロ酢酸塩の合成
工程１
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロパンアミド二トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩、（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロピオン酸を出発原料とし実施例１２４の工程５と同様の操作により表題化合物を得た。
工程２
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−イミダゾリル）プロパンアミド二トリフルオロ酢酸塩の合成
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロパンアミド 二トリフルオロ酢酸塩４０ｍｇ（０．０５ｍｍｏｌ）、１-トヒドロキシベンズトリアゾール１３．５ｍｇ（０．１ｍｍｏｌ）をテトラヒドロフラン２ｍｌに溶解し、室温で一晩撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ２３ｍｇ（０．０３５ｍｍｏｌ） 収率 ７０％
MS(ESI,m/z)431(MH+)
H-NMR(DMSO-d6)δ1.35(9H,s),1.85(2H,tt),2.80-3.10(2H,m),3.25(2H,dt),4.05(2H,t),4.20(1H,m),7.11(1H,d),7.26-7.40(4H,m),7.53(1H,t),8.03(1H,br),8.95(1H,s),9.15(2H,br),9.25(2H,br)
実施例１３３
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）−３−（４−イミダゾリル）プロパンアミド二トリフルオロ酢酸塩の合成
工程１
（２Ｓ）−２−アミノ−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロピオン酸 二トリフルオロ酢酸塩の合成
（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロピオン酸５ｇをトリフルオロ酢酸中、室温で２時間撹拌した。溶媒を留去し、残渣をジクロロメタンに懸濁して濾取、真空乾燥により表題化合物を得た。
収量 ６．００ｇ
H-NMR(DMSO-d6)δ2.40(3H,s),3.00(2H,m),4.18(1H,brs),7.48-7.56(3H,m),7.96(2H,d),8.20(3H,brs),8.36(1H,d)
工程２
（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロピオン酸 の合成
（２Ｓ）−２−アミノ−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロピオン酸 二トリフルオロ酢酸塩１ｇ（２．４ｍｍｏｌ）、炭酸水素ナトリウム８４０ｍｇ（１０ｍｍｏｌ）を水３０ｍｌに溶解し、そこへベンジルクロロホルマート２．４ｍｌ（１５ｍｍｏｌ）をエーテル３０ｍｌに溶解し加えた。室温で４時間撹拌した後に飽和炭酸水素ナトリウム水溶液を加えエーテルで水層を洗浄した。続いて水層に塩酸を加え酸性にし、酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により表題化合物を得た。
収量 ６２８ｍｇ
H-NMR(DMSO-d6)δ2.30(3H,s),2.90-3.20(2H,m),4.35(1H,brs),5.00-5.10(3H,m),7.12(2H,d),7.27-7.40(7H,m),7.49(2H,d)
工程３
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）−３−（４−イミダゾリル）プロパンアミド二トリフルオロ酢酸塩の合成
（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）−３−［１−（４−トルエンスルホニル）−４−イミダゾリル］プロピオン酸、３−（アミノプロポキシ）ベンズアミジン 二塩酸塩を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物を得た。
MS(ESI,m/z)465(MH+)
H-NMR(DMSO-d6)δ1.90(2H,tt),2.85-3.15(2H,m),3.25(2H,dt),4.05(2H,t),4.30(1H,m),4.95-5.05(2H,m),7.24-7.40(9H,m),7.53(1H,t),8.50(1H,br),8.96(1H,s),9.17(2H,brs),9.28(2H,brs)
実施例１３４
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ，３Ｓ）−２−（ベンジルオキシカルボニルアミノ）−３−メチルペンタンアミド トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩７０ｍｇ（０．２８ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニル−Ｌ−イソロイシン７０ｍｇ（０．２６ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物を得た。
収量 ３３ｍｇ（０．０６ｍｍｏｌ） 収率 ２３％
MS(ESI,m/z)441(MH+)
H-NMR(DMSO-d6)δ0.78-0.83(6H,m),1.10(1H,m),1.40(1H,m),1.70(1H,m),1.90(2H,m),3.22(2H,m),3.80(1H,t),4.05(2H,t),5.00(2H,m),7.22-7.40(8H,m),7.55(1H,t),8.05(1H,br),9.03(2H,br),9.30(2H,br)
実施例１３５
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）−６−アミノヘキサンアミド 二トリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩７０ｍｇ（０．２８ｍｍｏｌ）、Ｎ−α−ベンジルオキシカルボニル−Ｎ−ε−ｔ−ブトキシカルボニル−Ｌ−リジン９９ｍｇ（０．２６ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物のｔ−ブチルカルバマートを得た。続いてこのものを４規定塩化水素のジオキサン溶液に溶解し、５時間撹拌した。溶媒を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。収量 ７０ｍｇ（０．１ｍｍｏｌ） 収率 ３８％
MS(ESI,m/z)456(MH+)
H-NMR(DMSO-d6)δ1.30(2H,m),1.43-1.61(4H,m),1.90(2H,m),2.75(2H,m),3.23(2H,m),3.90(1H,m),4.05(2H,t),5.01(2H),7.26-7.41(8H,m),7.53(1H,t),7.69(3H,br),8.23(1H,br),9.15(2H,br),9.30(2H,br)
実施例１３６
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）−３−フェニルプロパンアミドトリフルオロ酢酸塩の合成
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩３０ｍｇ（０．１１ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニル−Ｌ−フェニルアラニン４０ｍｇ（０．１３５ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物を得た。
収量 ７ｍｇ（０．０１２ｍｍｏｌ） 収率 ９％
MS(ESI,m/z)475(MH+)
H-NMR(DMSO-d6)δ1.82(2H),2.70-3.00(2H,m),3.23(2H,m),4.00(2H,t),4.20(1H,m),4.90-5.00(4H,m),7.17-7.40(12H,m),7.50-7.60(2H),8.10(1H,br),9.10(2H,br),9.30(2H,br)
実施例１３７
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｒ）−２−（ベンジルオキシカルボニルアミノ）−３−フェニルプロパンアミド トリフルオロ酢酸塩
３−（アミノプロポキシ）ベンズアミジン 二塩酸塩７０ｍｇ（０．２８ｍｍｏｌ）、Ｎ−ベンジルオキシカルボニル−Ｄ−フェニルアラニン７８ｍｇ（０．２６ｍｍｏｌ）を出発原料とし、実施例１２４の工程５と同様の操作により表題化合物を得た。
収量 １４．１ｍｇ（０．０２４ｍｍｏｌ） 収率 ９％
MS(ESI,m/z)475(MH+)
H-NMR(DMSO-d6)δ1.82(2H),2.70-3.00(2H,m),3.23(2H,m),4.00(2H,t),4.20(1H,m),4.90-5.00(4H,m),7.17-7.40(12H,m),7.50-7.60(2H),8.10(1H,br),9.05(2H,br),9.30(2H,br)
実施例１３８
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−アミノプロパンアミド 二トリフルオロ酢酸塩の合成
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）プロパンアミド トリフルオロ酢酸塩１１ｍｇ（０．０２ｍｌｏｌ）をエタノール１ｍｌに溶解し、１０％パラジウム炭素１ｍｇを加え、１気圧の水素雰囲気下、室温で５時間撹拌した。吸引濾過によりパラジウム炭素を除き、濾液にトリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水を加えた後、濃縮して表題化合物を得た。
収量 ７ｍｇ（０．０１４ｍｍｏｌ） 収率 ７０％
MS(ESI,m/z)349(MH+ +DMSO-d6)
H-NMR(DMSO-d6)δ1.35(3H,d),1.90(2H,tt),3.30(2H,dt),3.80(1H,br),4.10(2H,t),7.30(1H,d),7.37(1H,s),7.39(1H,d),7.54(1H,t),8.12(3H,br),8.52(1H,br),9.31(2H,br),9.37(2H,br)
実施例１３９
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−アミノ−３−（４−イミダゾリル）プロパンアミド 三トリフルオロ酢酸塩の合成
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−イミダゾリル）プロパンアミド二トリフルオロ酢酸塩１０ｍｇを４規定塩化水素のジオキサン溶液に溶解し、２時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ７ｍｇ（０．０１０ｍｍｏｌ） 収率 ６７％
MS(ESI,m/z)331(MH+)
H-NMR(DMSO-d6)δ1.85(2H,m),3.15(2H,m),3.30(2H,dt),4.02-4.12(3H,m),7.28(1H,d),7.34-7.42(3H,m),7.54(1H,t),8.40(3H,br),8.60(1H,br),8.85(1H,s),9.30(4H,br)
実施例１４０
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ，３Ｓ）−２−アミノ−３−メチルペンタンアミド 二トリフルオロ酢酸塩の合成
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ，３Ｓ）−２−（ベンジルオキシカルボニルアミノ）−３−メチルペンタンアミドトリフルオロ酢酸塩２８ｍｇ（０．０５０ｍｍｏｌ）を出発原料とし、実施例１３８と同様の操作により表題化合物を得た。
収量 ２５ｍｇ（０．０４７ｍｍｏｌ） 収率 ９４％
MS(ESI,m/z)307(MH+)
H-NMR(DMSO-d6)δ0.80-0.90(6H,m),1.05(1H,m),1.43(1H,m),1.80(1H,m),1.95(2H,m),3.20-3.40(2H,m),3.55(1H,br),4.10(2H,t),7.29(2H,d),7.37(1H,s),7.39(1H,d),7.55(1H,t),8.13(3H,br),8.55(1H,br),9.28(2H,br),9.32(2H,br)
実施例１４１
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２，６−ジアミノヘキサンアミド 三トリフルオロ酢酸塩の合成
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｓ）−２−（ベンジルオキシカルボニルアミノ）−６−アミノヘキサンアミド 二トリフルオロ酢酸塩２０ｍｇ（０．０３ｍｍｏｌ）を出発原料とし、実施例１３８と同様の操作により表題化合物を得た。
収量 １７ｍｇ（０．０２６ｍｍｏｌ） 収率 ８７％
MS(ESI,m/z)322(MH+)
H-NMR(DMSO-d6)δ1.35(2H,m),1.55(2H,m),1.70(2H,m),1.90(2H,tt),2.75(2H,br),3.30(2H,dt),3.60-3.90(1H),4.10(2H,t),7.28(2H,d).7.38(2H,s),7.40(2H,d),7.54(1H,t),7.90(3H,br),8.24(3H,br),8.66(1H,br),9.34(2H,br),9.53(2H,br)
実施例１４２
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｒ）−２−アミノ−３−フェニルプロパンアミド 二トリフルオロ酢酸塩の合成
Ｎ−［３−（３−アミジノフェノキシ）プロピル］−（２Ｒ）−２−（ベンジルオキシカルボニルアミノ）−３−フェニルプロパンアミド 二トリフルオロ酢酸塩１０ｍｇ（０．０１７ｍｍｏｌ）を出発原料とし、実施例１３８と同様の操作により表題化合物を得た。
収量 ８ｍｇ（０．０１４ｍｍｏｌ） 収率 ８２％
MS(ESI,m/z)349(MH+)
H-NMR(DMSO-d6)δ1.75(2H,m),3.00(2H,d),3.05-3.35(2H,m),3.85-4.00(3H,m),7.20-7.34(7H,m),7.40(1H,d),7.54(1H,t),8.28(3H,br),8.50(1H,br),9.31(2H,br),9.38(2H,br)
実施例１４３
Ｎ−［２−（３−アミジノフェニルチオ）エチル］−４−アミジノベンズアミド二トリフルオロ酢酸塩の合成
工程１
ベンジル−Ｎ−（２−ブロモエチル）カルバマートの合成
２−ブロモエチルアミン臭素酸塩１０ｇ（４９ｍｍｏｌ）、トリエチルアミン１５ｍｌをジクロロメタンに溶解し、ベンジルクロロホルマート７．８ｍｌ（４９ｍｍｏｌ）を氷冷下加え、室温で撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １０．６ｇ（４１ｍｍｏｌ） 収率 ８４％
H-NMR(CDCl3)δ3.45(2H,t),3.60(2H,dt),5.10(2H,s),5.20(1H,brs),7.30-7.38(5H,m)
工程２
３−メルカプトベンゾニトリルの合成
３−アミノベンゾニトリル２ｇ（１７ｍｍｏｌ）を６規定塩化水素に懸濁させ、亜硝酸ナトリウム１．１７ｇ（１７ｍｍｏｌ）を冷水に溶かして４℃以下を保ちながら加えた。この反応液をＯ−エチルジチオ炭酸カリウム３．０４ｇ（１９ｍｍｏｌ）の水溶液を４５℃に熱したものへ注ぎ、４５℃で更に２時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製しジチオ炭酸−Ｏ−エチル−Ｓ−（３-シアノフェニル）を得た。
続いて、このものをアルゴン雰囲気下エタノールに溶解し、加熱環流した後、水酸化カリウム５００ｍｇを加え、再び４時間加熱環流した。溶媒を留去し得られた残留物を酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ４４６ｍｇ（３．３０ｍｍｏｌ） 収率 １９％
H-NMR(CDCl3)δ3.60(1H,s),7.33(1H,t),7.44(1H,d),7.49(1H,d),7.54(1H,s)
工程３
３−［２−（ベンジルオキシカルボニルアミノ）エチルチオ］ベンゾニトリルの合成
３−メルカプトベンゾニトリル４４０ｍｇ（３．３ｍｍｏｌ）、炭酸カリウム４６０ｍｇ（３．３ｍｍｏｌ）、Ｎ−ベンジル−（２−ブロモエチル）カルバマート１．０ｇ（４ｍｍｏｌ）、テトラブチルアンモニウムブロミド１６０ｍｇ（０．５ｍｍｏｌ）をジメチルホルムアミドに溶解し、アルゴン雰囲気下室温で４時間撹拌した。溶媒を留去して得られた残留物を酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ４１４ｍｇ（１．３ｍｍｏｌ） 収率 ３９％
H-NMR(CDCl3)δ3.10(2H,t),3.40(2H,dt),5.10(3H,brs),7.31-7.40(6H,m),7.45(1H,d),7.57(1H,brd),7.59(1H,brs)
工程４
（２−アミノエチルチオ）ベンゾニトリル 塩酸塩の合成
３−［２−（ベンジルオキシカルボニルアミノ）エチルチオ］ベンゾニトリル４００ｍｇ（１．２６ｍｍｏｌ）を２０％臭化水素を含む酢酸に溶解し、室温で２時間撹拌した。溶媒を留去して得られた残留物を１規定塩化水素にとかし酢酸エチルで洗浄後、１規定水酸化ナトリウム水溶液でアルカリ性とし、続いて、酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。収量 １９０ｍｇ（１．１ｍｍｏｌ） 収率 ８４％
H-NMR(CDCl3)δ2.95(2H,t),3.05(2H,t),7.38(1H,t),7.45(1H,d),7.55(1H,d),7.59(1H,s)
工程５
Ｎ−［２−（３−シアノフェニルチオ）エチル］−４−シアノベンズアミドの合成
（２−アミノエチルチオ）ベンゾニトリル 塩酸塩１９０ｍｇ（１．１ｍｍｏｌ）、４−シアノ安息香酸１７７ｍｇ（１．２ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作により表題化合物を得た。
収量 ２２３ｍｇ（０．７３ｍｍｏｌ） 収率 ６６％
H-NMR(CDCl3)δ3.25(2H,t),3.70(2H,dt),6.50(1H,brt),7.40(1H,t),7.43(1H,d),7.61(1H,d),7.64(1H,s),7.75(2H,d),7.83(2H,d)
工程６
Ｎ−［２−（３−アミジノフェニルチオ）エチル］−４−アミジノベンズアミドの合成
Ｎ−［２−（３−シアノフェニルチオ）エチル］−４−シアノベンズアミド２１０ｍｇ（０．６８ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作により表題化合物を得た。収量 １３７ｍｇ（０．２４ｍｍｏｌ） 収率 ３５％
MS(ESI,m/z)342(MH+)
H-NMR(DMSO-d6)δ3.30(2H,t),3.55(2H,m),7.57(1H,t),7.60(1H,d),7.75(1H,d),7.80(1H,s),7.91(2H,d),8.02(2H,d),9.03(1H,brt),9.26(2H,brs),9.31(4H,brs),9.41(2H,brs)
実施例１４４
Ｎ−［３−（３−アミジノフェニル）プロピル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
３−（３−ブロモプロピル）ベンゾニトリルの合成
３−（３−シアノフェニル）プロピオン酸１．５ｇ（８．５６ｍｍｏｌ）、トリエチルアミン１．１９ｍｌ（８．５６ｍｍｏｌ）をテトラヒドロフラン４２ｍｌに溶解し、氷冷下クロロギ酸エチル０．８１９ｍｌ（８．５６ｍｍｏｌ）を加え２０分間撹拌した。生じた析出物を吸引濾過により除去し、濾液に氷３ｇ、水素化ホウ素ナトリウム０．６４８ｇ（１７．１２ｍｍｏｌ）を氷冷下加え１時間撹拌した。ここに１規定塩化水素水溶液を２０ｍｌを加え室温で更に１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた油状残渣をジクロロメタン８６ｍｌに溶解し、四臭化炭素５．６８ｇ（１７．１２ｍｍｏｌ）、トリフェニルホスフィン２．６９ｇ（１０．２７ｍｍｏｌ）を加え室温で１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．４８ｇ（６．５９ｍｍｏｌ） 収率 ７７％
工程２
Ｎ−［３−（３−シアノフェニル）プロピル］−４−シアノベンズアミドの合成
アルゴン雰囲気下、水素化ナトリウム（６５％）２６７ｍｇ（７．２３ｍｍｏｌ）をＤＭＦ８ｍｌに溶解し、ジ−ｔ−ブチル イミノジカルボキシラート１．４３ｇ（６．５７ｍｍｏｌ）を加え室温で３０分間撹拌した。ここに３−（３−ブロモプロピル）ベンゾニトリル１．４７ｇ（６．５７ｍｍｏｌ）を加え４５℃で３時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた油状残渣を４規定塩化水素のジオキサン溶液に溶解し、室温で４時間撹拌した。溶媒を留去し得られた油状残渣をジクロロメタン１０ｍｌに溶解し４−シアノ安息香酸クロリド１．６３ｇ（９．８６ｍｍｏｌ）、トリエチルアミン１．８３ｍｌ（１３．４ｍｍｏｌ）を加え室温で５時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．３５ｇ（４．６６ｍｍｏｌ） 収率 ７１％
H-NMR(CDCl3)δ1.98(2H,quint),2.76(2H,t),3.50(2H,dt),6.94(1H,br),7.36-7.50(4H,m),7.69(2H,d),7.89(2H,d)
工程３
Ｎ−［３−（３−アミジノフェニル）プロピル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［３−（３−シアノフェニル）プロピル］−４−シアノベンズアミド８００ｍｇ（２．７６ｍｍｏｌ）を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール８ｍｌに加え、室温で一晩撹拌した。続いて室温でアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液３０ｍｌに溶解して室温で一晩撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １３０ｍｇ（０．２３６ｍｍｏｌ） 収率 ８．５％
MS(ESI,m/z)324(MH+)
H-NMR(DMSO-d6)δ1.91(2H,quint),2.75(2H,t),3.34(2H,dt),7.50-7.70(4H,m),7.89(2H,d),8.03(2H,d),8.79(1H,t),9.14(2H,s),9.27(4H,s),9.40(2H,s)
実施例１４５
Ｎ−［（２Ｅ）−３−（３−アミジノフェニル）−２−プロペニル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
３−［（１Ｅ）−３−ブロモ−１−プロペニル］ベンゾニトリルの合成
（３Ｅ）−３−（３−シアノフェニル）アクリル酸２．５ｇ（１４．４ｍｍｏｌ）を出発原料とし、３−（３−ブロモプロピル）ベンゾニトリルの合成と同様の操作に従い表題化合物を得た。収量 ３．０４ｇ（１３．６８ｍｍｏｌ） 収率 ９５％
工程２
Ｎ−［（２Ｅ）−３−（３−シアノフェニル）−２−プロペニル］−４−シアノベンズアミドの合成
３−［（１Ｅ）−３−ブロモ−１−プロペニル］ベンゾニトリル３．６５ｇ（１６．４４ｍｍｏｌ）を出発原料とし、Ｎ−［３−（３−シアノフェニル）プロピル］−４−シアノベンズアミドの合成と同様の操作に従い表題化合物を得た。
収量 ３．０２ｇ（１０．５２ｍｍｏｌ） 収率 ６４％
H-NMR(CDCl3)δ4.27(1H,dd),6.35(1H,dt),6.56(1H,d),7.16(1H,br),7.37-7.59(4H,m),7.72(2H,d),7.96(2H,d)
工程３
Ｎ−［（２Ｅ）−３−（３−アミジノフェニル）−２−プロペニル］４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［（２Ｅ）−３−（３−シアノフェニル）−２−プロペニル］−４−シアノベンズアミド７８０ｍｇ（２．７１ｍｍｏｌ）を出発原料としＮ−［３−（３−アミジノフェニル）プロピル］−４−アミジノベンズアミドの合成と同様の操作に従い表題化合物を得た。
収量 ３３ｍｇ（０．０６ｍｍｏｌ） 収率 ２．２％
MS(ESI,m/z)322(MH+)
H-NMR(DMSO-d6)δ4.15(2H,t),6.55(1H,dt),6.65(1H,d),7.58(1H,dd),7.68(1H,d),7.79(1H,d),7.89(1H,s),7.92(2H,d),8.10(2H,d),9.10(1H,t),9.21(2H,s),9.32(4H,s),9.41(2H,s)
実施例１４６
Ｎ−［２−（５−アミジノ−２−ヨードフェノキシ）エチル］−４−アミジノベンズアミド二トリフルオロ酢酸塩の合成
工程１
３−ヒドロキシ−４−ヨード安息香酸の合成
３−ヒドロキシ安息香酸３０．０ｇ（２１７ｍｍｏｌ）を酢酸２００ｍｌに溶解し、一塩化ヨウ素５３．０ｇ（３２６ｍｍｏｌ）を室温で加えた。４５℃で１５時間撹拌後、溶媒を減圧留去して得た残渣を１％チオ硫酸ナトリウム水溶液５００ｍｌで２回、水５００ｍｌで２回洗浄し、８０℃で減圧乾固させることで、表題化合物を得た。
収量 １７．２ｇ（６５．２ｍｍｏｌ） 収率 ３０％
MS(FAB,m/z)265(MH+)
H-NMR(DMSO-d6)δ7.13(1H,dd),7.43(1H,d),7.80(1H,d)
工程２
３−ヒドロキシ−４−ヨードベンゾニトリルの合成
３−ヒドロキシ−４−ヨード安息香酸２２．３ｇ（８９．７ｍｍｏｌ）をテトラヒドロフラン３００ｍｌに溶解したものにクロロギ酸エチル１９．７ｍｌ（２０６ｍｍｏｌ）、トリエチルアミン２８．７ｍｌ（２０６ｍｍｏｌ）を０℃で加えた。１５分撹拌後、生成したトリエチルアミン塩酸塩を濾別し、アンモニアをバブリングして得られたテトラヒドロフラン溶液３００ｍｌに、濾液を０℃で加えた。室温で１０時間撹拌後、溶媒を減圧留去して得られた残留物をジオキサン４５０ｍｌに溶解し無水トリフルオロメタンスルホン酸１７．４ｍｌ（１１７ｍｍｏｌ）、ピリジン２１．８ｍｌ（２６９ｍｍｏｌ）を０℃で加えた。室温で１８時間撹拌後、溶媒を減圧留去して得られた残留物をクロロホルムを抽出溶媒とし常法に従って処理し油状残渣を得た。得られた残留物をテトラヒドロフラン：メタノール（１：１）１８０ｍｌに溶解したものに１規定水酸化ナトリウム水溶液９０ｍｌ（９０．０ｍｍｏｌ）を室温で加えた。そのまま４時間撹拌後、溶媒を減圧留去し、得られた残留物をジクロロメタンで洗浄した。続いて、１規定塩化水素で酸性とし酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ９．２９ｇ（３７．９ｍｍｏｌ） 収率 ４２％
MS(FAB,m/z)246(MH+)
H-NMR(CDCl3)δ5.63(1H,br),6.96(1H,dd),7.23(1H,d),7.79(1H,d)
工程３
３−（２−アミノエトキシ）−４−ヨードベンゾニトリルの合成
３−ヒドロキシ−４−ヨードベンゾニトリル７．４４ｇ（３０．４ｍｍｏｌ）、Ｎ−ｔ−ブチル−２−クロロエチルカルバマート６．５２ｇ（３６．４ｍｍｏｌ）を出発原料とし、実施例１の工程２及び工程３と同様の操作に従い表題化合物を得た。
収量 ４．９０ｇ（１７．０ｍｍｏｌ） 収率 ５６％
MS(ESI,m/z)289(MH+)
H-NMR(DMSO-d6)δ2.90(2H,t),4.06(2H,t),7.18(1H,dd),7.45(1H,d),7.99(1H,d)
工程４
Ｎ−［２−（５−シアノ−２−ヨードフェノキシ）エチル］−４−シアノベンズアミドの合成 ３−（２−アミノエトキシ）−４−ヨードベンゾニトリル８００ｍｇ（２．４７ｍｍｏｌ）、４−シアノ安息香酸４３６ｍｇ（２．９６ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作に従い表題化合物を得た。
収量 ９４０ｍｇ（２．２５ｍｍｏｌ） 収率 ９１％
MS(ESI,m/z)418(MH+)
H-NMR(CDCl3)δ2.90(2H,t),4.06(2H,t),7.18(1H,dd),7.45(1H,d),7.99(1H,d)
工程５
Ｎ−［２−（５−アミジノ−２−ヨードフェノキシ）エチル］−４−アミジノベンズアミド二トリフルオロ酢酸塩の合成
Ｎ−［２−（５−シアノ−２−ヨードフェノキシ）エチル］−４−シアノベンズアミド２００ｍｇ（０．４８ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作に従い表題化合物を得た。
収量 ９３ｍｇ（０．１４ｍｍｏｌ） 収率 ２９％
MS(ESI,m/z)452(MH+)
H-NMR(DMSO-d6)δ3.74(2H,dt),4.33(2H,t),7.18(1H,d),7.41(1H,s),7.90(2H,d),8.03(1H,d),8.06(2H,d),8.96(1H,t),9.10(2H,br),9.16(2H,br),9.33(2H,br),9.40(2H,br),
実施例１４７
３−［４−アミジノ−２−［２−（４−アミジノフェニルカルバモイル）エトキシ］フェニル］−２−オキソプロピオン酸 二トリフルオロ酢酸塩の合成
Ｎ−［２−（５−アミジノ−２−ヨードフェノキシ）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩５０ｍｇ（０．０７４ｍｍｏｌ）をＤＭＦ０．５ｍｌに溶解し、ジ−ｔ−ブチルジカーボネート３５ｍｇ（０．１６ｍｍｏｌ）、トリエチルアミン０．０５ｍｌ（０．３７ｍｍｏｌ）を０℃で加え、４時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し、得られた化合物をアセトニトリル０．８ｍｌに溶解し、メチル−２−アセタミドアクリレート２７ｍｇ（０．１９ｍｍｏｌ）、酢酸パラジウム２ｍｇ（０．００９５ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン５．８ｍｇ（０．００１９ｍｍｏｌ）、トリブチルアミン０．０６ｍｌ（０．２２ｍｍｏｌ）を室温で加えた。アルゴン雰囲気下、９０℃で２１時間撹拌後、吸引濾過し、濾液を減圧留去した。得られた残留物に３規定塩化水素５ｍｌを室温で加え、６０℃で３０分、さらに１１０℃で３０分撹拌した。溶媒を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。収量 ４．６ｍｇ（０．００７２ｍｍｏｌ） 収率 ９．７％
MS(FAB,m/z)412(MH+)
H-NMR(DMSO-d6)δ3.72(2H,dt),4.15(2H,s,keto form),4.31(2H,t),6.81(1H,s,enol form),7.36-7.48(2H,m),7.88(2H,d),8.04(2H,d),8.33(1H,d),9.02(1H,t),9.07(2H,m),9.25(4H,br),9.40(2H,br)
実施例１４８
Ｎ−［２−（５−アミジノ−２−メチルフェノキシ）エチル］−４−アミジノベンズアミド二トリフルオロ酢酸塩の合成
工程１
３−ヒドロキシ−４−メチルベンゾニトリルの合成
３−ヒドロキシ−４−メチル安息香酸２９．８ｇ（１９６ｍｍｏｌ）をテトラヒドロフラン４５０ｍｌに溶解し、クロロギ酸エチル４３．１ｍｌ（４５０ｍｍｏｌ）、トリエチルアミン６２．７ｍｌ（４５０ｍｍｏｌ）を０℃で加えた。２０分撹拌後、生成したトリエチルアミン塩酸塩を濾別し、アンモニアをバブリングして得られたテトラヒドロフラン溶液３００ｍｌに濾液を０℃で加えた。室温で２時間撹拌後、溶媒を減圧留去して得られた残留物をジオキサン５００ｍｌに溶解し無水トリフルオロメタンスルホン酸３８．８ｍｌ（２７４ｍｍｏｌ）、ピリジン７５ｍｌ（９３１ｍｍｏｌ）を０℃で加えた。室温で１８時間撹拌後、溶媒を減圧留去して得られた残留物をクロロホルムを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。得られた残留物をテトラヒドロフラン：メタノール（１：１）３３０ｍｌに溶解したものに１規定水酸化ナトリウム水溶液１６５ｍｌ（１６７ｍｍｏｌ）を室温で加えた。そのまま４時間撹拌後、溶媒を減圧留去し、得られた残留物をジクロロメタンで洗浄した。続いて、１規定塩化水素で酸性とし酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ２０．１ｇ（１５１ｍｍｏｌ） 収率 ７７％
MS(FAB,m/z)134(MH+)
H-NMR(CDCl3)δ2.30(3H,s),5.93(1H,s),7.08(1H,s),7.14(1H,d),7.21(1H,d)
工程２
３−（２−アミノエトキシ）−４−メチルベンゾニトリルの合成
３−ヒドロキシ−４−メチルベンゾニトリル１３．７ｇ（１０３ｍｍｏｌ）、
Ｎ−ｔ−ブチル−２−クロロエチルカルバマート２２．２ｇ（１２４ｍｍｏｌ）を出発原料とし、実施例１の工程２及び工程３と同様の操作に従い表題化合物を得た。
収量 ６．１３ｇ（３４．８ｍｍｏｌ） 収率 ３４％
MS(ESI,m/z)261(M+DMSO+H+)
H-NMR(CDCl3)δ2.29(3H,s),3.14(2H,t),4.01(2H,t),7.03(1H,d),7.17(1H,dd),7.22(1H,d)
工程３
Ｎ−［２−（５−シアノ−２−メチルフェノキシ）エチル］−４−シアノベンズアミドの合成 ３−（２−アミノエトキシ）−４−メチルベンゾニトリル６．１３ｇ（３４．８ｍｍｏｌ）、４−シアノ安息香酸６．１４ｇ（４１．８ｍｍｏｌ）、クロロギ酸エチル３．７ｍｌ（３８．３ｍｍｏｌ）を出発原料とし、実施例１の工程４と同様の操作に従い表題化合物を得た。
収量 １３．９ｇ（４５．６ｍｍｏｌ） 収率 ＞１００％
MS(FAB,m/z)306(MH+)
H-NMR(CDCl3)δ2.28(3H,s),3.95(2H,dd),4.19(2H,t),7.05(1H,s),7.22(2H,s),7.76(2H,d),7.88(2H,d)
工程４
Ｎ−［２−（５−アミジノ−２−メチルフェノキシ）エチル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
Ｎ−［２−（５−シアノ−２−メチルフェノキシ）エチル］−４−シアノベンズアミド２．００ｇ（６．５５ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作に従い表題化合物を得た。
収量 ９１４ｍｇ（１．６１ｍｍｏｌ） 収率 ２５％
MS(ESI,m/z)340(MH+)
H-NMR(DMSO-d6)δ2.23(3H,s),3.73(2H,d),4.26(2H,t),7.36(1H,d),7.37(1H,s),7.41(1H,d),7.90(2H,d),8.05(2H,d),8.93(2H,br),9.02(1H,br),9.11(2H,br),9.24(2H,br),9.41(2H,br),
実施例１４９
Ｎ−［５−アミジノ−２−［２−（２−フリル）−２−オキソエチル］フェノキシ］エチル−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
工程１
Ｎ−［２−（５−シアノ−２−ブロモメチルフェノキシ）エチル］−４−シアノベンズアミドの合成
Ｎ−［２−（５−シアノ−２−メチルフェノキシ）エチル］−４−シアノベンズアミド１２．０ｇ（３９．３ｍｍｏｌ）を四塩化炭素２００ｍｌに溶解し、Ｎ−ブロモスクシンイミド７．００ｇ（３９．３ｍｍｏｌ）、アゾイソブチロニトリル７００ｍｇ（４．２６ｍｍｏｌ）を加えた。１００℃で３日間撹拌後、Ｎ−ブロモスクシンイミド１６．８ｇ（９４．４ｍｍｏｌ）、アゾイソブチロニトリル２．１ｇ（１２．８ｍｍｏｌ）をさらに加え２日間撹拌た。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １１．９６ｇ（３１．２ｍｍｏｌ） 収率 ７９％
MS(FAB,m/z)384(MH+)
H-NMR(CDCl3)δ4.00(2H,dd),4.30(2H,t),4.55(2H,s),7.14(1H,d),7.26(1H,dd),7.42(1H,d),7.72(2H,d),7.82(2H,d)
工程２
Ｎ−［５−アミジノ−２−［２−（２−フリル）−２−オキソエチル］フェノキシ］エチル−４−アミジノベンズアミド 二トリフルオロ酢酸塩の合成
テトラキストリフェニルホスフィンパラジウム２３０ｍｇ（０．２０ｍｍｏｌ）、粉末亜鉛８５ｍｇ（１．３０ｍｍｏｌ）にアルゴン雰囲気下、アセトニトリル５ｍｌ、２−フロイルクロリド０．２ｍｌ（２．０ｍｍｏｌ）を加えたものに、アセトニトリル５ｍｌに溶解したＮ−［２−（５−シアノ−２−ブロモメチルフェノキシ）エチル］−４−シアノベンズアミド３８３ｍｇ（１．０ｍｍｏｌ）を室温で加え、そのまま２４時間撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、得られた化合物を実施例９５の工程５と同様の操作に従い表題化合物を得た。
収量 ６．６ｍｇ（０．０１０ｍｍｏｌ） 収率 １．０％
MS(ESI,m/z)434(MH+)
H-NMR(DMSO-d6)δ3.58(2H,dd),4.19(2H,t),4.28(2H,s),6.68(1H,dd),7.38-7.41(1H,m),7.42(1H,d),7.43(1H,s),7.48(1H,dd),7.88(2H,d),7.96(2H,d),7.99-8.05(1H,m),8.80(1H,t),9.13(2H,br),9.28(4H,br),9.41(2H,br)
keto form 100%
実施例１５０
３−［（２Ｓ）−２−アミノ−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 三トリフルオロ酢酸塩の合成
３−［（２Ｓ）−２−アミノ−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
工程１
４−ヒドロキシピペリジン−１−カルボン酸ベンジルの合成
４−ヒドロキシピペリジン２５．０ｇ（２４７ｍｍｏｌ）をジクロロメタン８００ｍｌに溶解し、０℃でカルボベンジルオキシクロリド３８ｍｌ（２６６ｍｍｏｌ）、トリエチルアミン７５ｍｌ（５３８ｍｍｏｌ）を加えた後、室温で１５時間撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し油状残渣を得た。このものは精製することなく次の反応に用いた。
収量 ４４．６ｇ（２０３ｍｍｏｌ） 収率 ８２％
工程２
（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−ヒドロキシフェニル）プロピオン酸メチルの合成
Ｌ−チロシンメチルエステル塩酸塩１５．２ｇ（６５．６ｍｍｏｌ）をジクロロメタン２００ｍｌに溶解し、室温でトリエチルアミン２０ｍｌ（１４３ｍｍｏｌ）、ジ−ｔ−ブチルジカーボネート１３．１ｇ（６０．０ｍｍｏｌ）をジクロロメタン５０ｍｌに溶解したものを加え、１５時間撹拌した。ジクロロメタンを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。このものは精製することなく次の反応に用いた。
収量 １９．２ｇ（６５．２ｍｍｏｌ） 収率 ９９％
工程３
（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロピオン酸メチルの合成
４−ヒドロキシピペリジン−１−カルボン酸ベンジル１８．９ｇ（８６．２ｍｍｏｌ）、（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−ヒドロキシフェニル）プロピオン酸メチル２５．４ｇ（８６．２ｍｍｏｌ）、トリフェニルフォスフィン２７．１ｇ（１０３．４ｍｍｏｌ）をテトラヒドロフラン５００ｍｌに溶解しアゾジカルボン酸ジエチル３７．５ｇ（８６．２ｍｍｏｌ）を室温で加え、１５時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ３２．１ｇ（６２．６ｍｍｏｌ） 収率 ７３％
H-NMR(CDCl3)δ1.42(9H,s),1.70-1.84(2H,m),1.86-2.00(2H,m),2.91-3.10(2H,m),3.38-3.53(2H,m),3.70(3H,s),3.71-3.82(2H,m),4.40-4.44(1H,m)4.45-4.60(1H,m),4.93-5.00(1H,m),5.18(2H,s),6.92(2H,d),7.02(2H,d),7.13-7.21(5H,m)
工程４
４−［４−［（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−ヒドロキシプロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジルの合成
（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロピオン酸メチル１０．４ｇ（２０．３ｍｍｏｌ）をテトラヒドロフラン３０ｍｌ、メタノール３０ｍｌに溶解し、０℃で水素化ホウ素ナトリウム２．４４ｇ（６４．５ｍｍｏｌ）を加え、室温に戻して１５時間撹拌後、０℃で再び水素化ホウ素ナトリウム０．８２ｇ（２１．７ｍｍｏｌ）を加え、室温に戻して更に２時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ９．４５ｇ（１９．５ｍｍｏｌ） 収率 ９６％
H-NMR(CDCl3)δ1.44(9H,s),1.68-1.82(2H,m),1.84-1.98(2H,m),2.78(2H,d),3.29-3.95(7H,m),4.40-4.44(1H,m),5.14(2H,s),6.92(2H,d),7.12(2H,d),7.28-7.40(5H,m)
工程５
４−［４−［（２Ｓ）−３−クロロ−２−（ｔ−ブトキシカルボニルアミノ）プロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジルの合成
４−［４−［（２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−ヒドロキシプロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジル５．５ｇ（１１．３ｍｍｏｌ）をジクロロメタン６０ｍｌに溶解し、０℃でトリエチルアミン３．２ｍｌ（２２．６ｍｍｏｌ）、メタンスルホニルクロリド１．９５ｇ（１７．０ｍｍｏｌ）を加えた。４時間撹拌後、ジクロロメタンを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し油状残渣を得た。こうして得られた残留物をジメチルホルムアミド１２０ｍｌに溶解し、リチウムクロリド２．５７ｇ（６０．６ｍｍｏｌ）を加え、５０℃で１５時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ２．６０ｇ（５．１６ｍｍｏｌ） 収率 ４５％
H-NMR(CDCl3)δ1.44(9H,s),1.63-1.82(2H,m),1.83-2.00(2H,m),2.91-3.10(2H,m),2.83(2H,d),3.40-3.54(3H,m),3.57-3.63(1H,m),3.66-3.80(3H,m),4.40-4.52(1H,m),5.14(2H,s),6.92(2H,d),7.16(2H,d),7.13-7.21(5H,m)
工程６
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリルの合成
４−［４−［（２Ｓ）−３−クロロ−２−（ｔ−ブトキシカルボニルアミノ）プロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジル６．４ｇ（１２．７ｍｍｏｌ）をジメチルホルムアミド７０ｍｌに溶解し、３−シアノフェノール２．２７ｇ（１９．１ｍｍｏｌ）、炭酸カリウム３．５１ｇ（２５．４ｍｍｏｌ）を加え、７０℃で１５時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ５．０ｇ（８．５４ｍｍｏｌ） 収率 ６７％
H-NMR(CDCl3)δ1.44(9H,s),1.66-1.83(2H,m),1.84-2.00(2H,m),2.50-2.60(1H,m),2.82-2.93(1H,m),3.40-3.53(3H,m),3.58-3.63(1H,m),3.65-3.80(3H,m),4.40-4.53(1H,m),5.14(2H,s)6.92(2H,d),7.16(2H,d),7.13-7.21(5H,m)
工程７
３−［（２Ｓ）−２−アミノ−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 三トリフルオロ酢酸塩の合成
３−［（２Ｓ）−２−アミノ−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩１０ｍｇ（０．０１７１ｍｍｏｌ）を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール５ｍｌを加え、室温で２４時間撹拌した。続いて室温でアンモニアを３０％含有する（Ｗ／Ｖ）エタノール溶液１０ｍｌに溶解して室温で２４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。３−［（２Ｓ）−２−アミノ−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 三トリフルオロ酢酸塩：
収量 ２．２ｍｇ（０．００３１ｍｍｏｌ） 収率 １８．１％
MS(FAB,m/z)369(MH+)
H-NMR(DMSO-d6)δ1.65-1.85(2H,m),2.00-2.10(2H,m),2.82-3.60(6H,m),3.60-3.90(1H,m),3.93-4.01(1H,m),4.10-4.20(1H,m),4.58-4.62(1H,m),6.75(2H,d),6.98(2H,d),7.20-7.60(4H,m),8.10(3H,br),8.55(2H,br),9.08(2H,br),9.30(2H,br)３−［（２Ｓ）−２−アミノ−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩：
収量 ３．２ｍｇ（０．００４３８ｍｍｏｌ） 収率 ２５．６％
MS(ESI,m/z)503(MH+)
H-NMR(DMSO-d6)δ1.42-1.61(2H,m),1.83-1.97(2H,m),2.89-2.99(2H,m),3.20-3.62(3H,m),3.65-3.89(2H,m),3.95-4.05(1H,m),4.11-4.20(1H,m),4.50-4.60(1H,m),5.08(2H,s),6.98(2H,d),7.20(2H,d),7.30-7.60(9H,m),8.10(3H,br),9.05(2H,br),9.35(2H,br)
実施例１５１
３−［（２Ｒ）−２−アミノ−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 三トリフルオロ酢酸塩の合成
３−［（２Ｒ）−２−アミノ−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｒ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩３９．４ｍｇ（０．０６５７ｍｍｏｌ）を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール１０ｍｌを加え、室温で２４時間撹拌した。続いて室温でアンモニアを１０％含有する（Ｗ／Ｖ）エタノール溶液１０ｍｌに溶解して室温で２４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
３−［（２Ｒ）−２−アミノ−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 三トリフルオロ酢酸塩：
収量 ２．４ｍｇ（０．００３３８ｍｍｏｌ） 収率 ５．０５％
MS(ESI,m/z)369(MH+)
H-NMR(DMSO-d6)δ1.65-1.82(2H,m),1.95-2.11(2H,m),2.61-2.85(2H,m),3.02-4.10(7H,m),4.52-4.64(1H,m),6.70(2H,d),7.02(2H,d),7.20-7.35(5H,m),7.28-7.48(3H,m),7.55(1H,t),8.37(3H,br),9.22(2H,d),9.32(2H,br),9.47(2H,br)
３−［（２Ｒ）−２−アミノ−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩：
収量 ３．２ｍｇ（０．００４３８ｍｍｏｌ） 収率 ５．５３％
MS(ESI,m/z)503(MH+)
H-NMR(DMSO-d6)δ1.47-1.61(2H,m),1.85-1.96(2H,m),2.90-3.01(2H,m),3.20-3.35(2H,m),3.67-3.87(2H,m),3.95-4.05(1H,m),4.12-4.18(1H,m),5.08(2H,s),6.95(2H,d),7.20(2H,d),7.30-7.45(8H,m),7.57(1H,t),8.21(3H,br),9.18(2H,br),9.31(2H,br)
実施例１５２
３−［（２Ｓ）−２−（エタンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−２−（エタンスルフォニルアミノ）−３−［４−（エタンスルフォニルオキシ）フェニル］プロポキシ］ベンズアミジン トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（エタンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩２５ｍｇ（０．０４７９ｍｍｏｌ）、トリエチルアミン７２．６ｍｇ（０．７３５ｍｍｏｌ）をＤＭＦ５ｍｌに溶解し、室温でエタンスルホニルクロリド２１．３ｍｇ（０．１６６ｍｍｏｌ）を加えた後、室温で終夜撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。続いて実施例１５０と同様の操作を行い表題化合物を得た。３−［（２Ｓ）−２−（エタンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩：
収量 ４．８ｍｇ（０．００６９７ｍｍｏｌ） 収率 １４．６％
MS(ESI,m/z)461(MH+)
H-NMR(DMSO-d6)δ0.93(3H,t),1.68-1.82(2H,m),1.98-2.18(2H,m),2.58(2H,q),2.62-3.02(2H,m),3.02-3.50(5H,m),4.00(2H,d),4.55-4.62(1H,m),6.97(2H,d),7.22(2H,d),7.27-7.60(4H,m),8.21(1H,br),8.35(2H,br),9.10(2H,br),9.38(2H,br)３−［（２Ｓ）−２−（エタンスルフォニルアミノ）−３−［４−（エタンスルフォニルオキシ）フェニル］プロポキシ］ベンズアミジン トリフルオロ酢酸塩：
収量 １．６ｍｇ（０．００２７４ｍｍｏｌ） 収率 ５．９％
MS(ESI,m/z)470(MH+)
H-NMR(DMSO-d6)δ0.88(3H,t),1.38(3H,t),2.52-3.10(4H,m),3.46(2H,q),3.78-3.86(1H,m),4.15(2H,t),7.27(2H,d),7.30-7.40(2H,m),7.43(2H,d),7.46-7.58(2H,m),7.43(2H,d),7.46-7.58(2H,m),8.95(2H,br),9.32(2H,br)
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（エタンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸：収量 ２．８ｍｇ（０．００３９５ｍｍｏｌ） 収率 ８．１４％
MS(ESI,m/z)595(MH+)
H-NMR(DMSO-d6)δ0.93(3H,t),1.47-1.61(2H,m),1.85-1.96(2H,m),2.90-3.01(2H,m),3.20-3.35(2H,m),3.67-3.87(2H,m),3.95-4.05(1H,m),4.12-4.18(1H,m),5.08(2H,s),6.95(2H,d),7.20(2H,d),7.30-7.45(8H,m),7.57(1H,t),8.21(3H,br),9.18(2H,br),9.31(2H,br)
実施例１５３
３−［（２Ｓ）−２−（ブタンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−２−（ブタンスルフォニルアミノ）−３−［４−（ブタンスルフォニルオキシ）フェニル］プロポキシ］ベンズアミジン トリフルオロ酢酸の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ブタンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩２５ｍｇ（０．０４７９ｍｍｏｌ）、トリエチルアミン７２．６ｍｇ（０．７３５ｍｍｏｌ）をＤＭＦ５ｍｌに溶解し、室温でブタンスルホニルクロリド２０．０ｍｇ（０．１２８ｍｍｏｌ）を加えた後、室温で終夜撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。続いて実施例１５０と同様の操作を行い表題化合物を得た。
３−［（２Ｓ）−２−（ブタンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩：
収量 ２．０ｍｇ（０．００２７９ｍｍｏｌ） 収率 ５．８０％
MS(ESI,m/z)489(MH+)
H-NMR(DMSO-d6)δ0.82(3H,t),1.08-1.42(4H,m),1.70-1.84(2H,m),1.95-2.13(2H,m),2.58(2H,t),2.60-3.10(2H,m),3.20-3.58(4H,m),3.62-3.82(1H,m),3.92-4.10(2H,m),4.56-4.65(1H,m),5.08(2H,s),6.92(2H,d),7.24(2H,d),7.30-7.58(4H,m),8.10(1H,m),8.26(2H,br),9.05(2H,br),9.26(2H,br)
３−［（２Ｓ）−２−（ブタンスルフォニルアミノ）−３−［４−（ブタンスルフォニルオキシ）フェニル］プロポキシ］ベンズアミジン トリフルオロ酢酸：
収量 ２．９ｍｇ（０．００４５３ｍｍｏｌ） 収率 ９．５４％
MS(ESI,m/z)526(MH+)
H-NMR(DMSO-d6)δ0.76(3H,t),0.92(3H,t),1.10-1.82(10H,m),2.52-2.70(4H,m),2.71-3.10(2H,m),3.42-3.58(2H,m),3.76-3.88(1H,m),4.00-4.18(2H,m),7.20-7.60(8H,m),8.92(2H,br),9.28(2H,br)
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ブタンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸塩：収量 ２．８ｍｇ（０．００３８０ｍｍｏｌ） 収率 ８．００％
MS(ESI,m/z)623(MH+)
H-NMR(DMSO-d6)δ0.93(3H,t),1.25-1.98(4H,m),2.58(2H,t),2.62-3.00(2H,m),3.62-3.80(3H,m),3.95-4.12(2H,m),4.28-4.32(2H,m),4.48-4.60(1H,m),5.08(2H,s),6.92(2H,d),7.22(2H,d),7.30-7.46(8H,m),7.52-7.58(1H,m),8.97(2H,br),9.29(2H,br)
実施例１５４
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ベンゼンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩２５ｍｇ（０．０４７９ｍｍｏｌ）、トリエチルアミン７２．６ｍｇ（０．７３５ｍｍｏｌ）をＤＭＦ５ｍｌに溶解し、室温でブタンスルホニルクロリド２０．０ｍｇ（０．１１３ｍｍｏｌ）を加えた後、室温で終夜撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。続いて実施例１５０と同様の操作を行い表題化合物を得た。
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩：
収量 ３．７ｍｇ（０．００５０２ｍｍｏｌ） 収率 １０．５％
MS(ESI,m/z)509(MH+)
H-NMR(DMSO-d6)δ1.76-1.90(2H,m),2.03-2.17(2H,m),2.62(1H,dd),2.83(1H,dd),3.00-3.39(4H,m),3.58-3.64(1H,m),3.94(2H,d),4.52-4.64(1H,m),6.79(2H,d),7.01(2H,d),7.08-7.56(7H,m),7.64-7.70(2H,m),8.12(1H,d),9.14(2H,br),9.33(2H,br),9.38(2H,br)
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ベンゼンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸塩：
収量 ２．８ｍｇ（０．００３７０ｍｍｏｌ） 収率 ７．７９％
MS(ESI,m/z)643(MH+)
H-NMR(DMSO-d6)δ1.42-1.60(2H,m),1.86-1.97(2H,m),2.68(1H,dd),2.80(1H,dd),3.20-3.58(2H,m),3.58-3.64(1H,m),3.64-3.80(2H,m),3.94(2H,d),4.40-4.53(1H,m),5.06(2H,s),6.76(2H,d),6.96(2H,d),7.10-7.24(2H,m),7.32-7.54(10H,m),7.62-7.70(2H,m),8.08(1H,d),8.94(2H,br),9.26(2H,br)
実施例１５５
３−［（２Ｓ）−２−（２−ナフタレンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−２−（ブタンスルフォニルアミノ）−３−（４−ヒドロキシフェニル）プロポキシ］ベンズアミジン トリフルオロ酢酸の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（２−ナフタレンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩２５ｍｇ（０．０４７９ｍｍｏｌ）、トリエチルアミン７２．６ｍｇ（０．７３５ｍｍｏｌ）をＤＭＦ５ｍｌに溶解し、室温で２−ナフタレンスルホニルクロリド２０．０ｍｇ（０．０８８２ｍｍｏｌ）を加えた後、室温で終夜撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。続いて実施例１５０と同様の操作を行い表題化合物を得た。
３−［（２Ｓ）−２−（２−ナフタレンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩：
収量 ５．５ｍｇ（０．００６９９ｍｍｏｌ） 収率 １４．７％
MS(ESI,m/z)559(MH+)
H-NMR(DMSO-d6)δ1.70-1.91(2H,m),2.00-2.12(2H,m),2.62(1H,dd),2.82(1H,dd),2.94-3.24(4H,m),3.64-3.76(1H,m),3.95(2H,d),4.38-4.48(1H,m),6.65(2H,d),6.97(2H,d),6.92-7.04(1H,m),7.10-7.55(5H,m),7.60-7.70(3H,m),7.82(1H,d),7.92(1H,d),8.08(1H,d),8.22(1H,d),8.31(1H,s),9.17(2H,br),9.29(2H,br),9.34(2H,br)
３−［（２Ｓ）−２−（ブタンスルフォニルアミノ）−３−（４−ヒドロキシフェニル）プロポキシ］ベンズアミジン トリフルオロ酢酸：
収量 ２．１ｍｇ（０．００３５６ｍｍｏｌ） 収率 ７．５２％
MS(ESI,m/z)476(MH+)
H-NMR(DMSO-d6)δ2.58(1H,dd),2.76(1H,dd),3.60-3.70(1H,m),3.86(2H,d),6.49(2H,d),6.84(2H,d),6.94-7.02(1H,m),7.08(1H,s),7.29(1H,d),7.37(1H,dd),7.60-8.00(8H,m),8.08(1H,d),8.14(1H,d),8.94(2H,br),9.13(1H,s),9.20(2H,br)３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（２−ナフタレンスルフォニルアミノ）プロポキシ］ベンズアミジン トリフルオロ酢酸塩：
収量 ２．７ｍｇ（０．００３３５ｍｍｏｌ） 収率 １４．７％
MS(ESI,m/z)693(MH+)
H-NMR(DMSO-d6)δ1.40-1.58(2H,m),1.78-1.92(2H,m),2.60(1H,dd),2.80(1H,dd),3.20-3.40(2H,m),3.62-3.86(3H,m),3.95(2H,d),4.25-4.38(1H,m),5.07(2H,s),6.60(2H,d),6.93(2H,d),7.04-7.08(1H,m),7.14-7.18(1H,m),7.28-7.40(9H,m),7.58-7.64(3H,m),7.91(1H,d),7.94(1H,d),8.05(1H,d),8.16(1H,d),8.30(1H,s),8.90(2H,br),9.21(2H,br)
実施例１５７
３−［（２Ｒ）−２−（エタンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル トリフルオロ酢酸塩１１ｍｇ（０．０１８３ｍｍｏｌ）、トリエチルアミン７２．６ｍｇ（０．７３５ｍｍｏｌ）をＤＭＦ５ｍｌに溶解し、室温でエタンスルホニルクロリド１０．０ｍｇ（０．１６６ｍｍｏｌ）を加えた後、室温で終夜撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。続いて実施例１５０と同様の操作を行い表題化合物を得た。
収量 １．７６ｍｇ（０．００２５６ｍｍｏｌ） 収率 １４．０％
MS(ESI,m/z)461(MH+)
H-NMR(DMSO-d6)δ0.94(3H,t),1.68-1.83(2H,m),2.00-2.16(2H,m),2.58(2H,q),2.70(1H,dd),2.95(1H,dd),2.98-3.38(4H,m),3.68-3.81(1H,m),4.01-4.04(2H,m),4.58-4.61(1H,m),6.95(2H,m),7.25(2H,m),7.40-7.60(4H,m),8.42(2H,br),8.90(2H,br),9.11(2H,br)
実施例１５７
３−［（２Ｒ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル トリフルオロ酢酸塩１１ｍｇ（０．０１８３ｍｍｏｌ）、ピリジン４．３ｍｇ（０．１０ｍｍｏｌ）をＤＭＦ２．５ｍｌに溶解し、室温でベンゼンスルホニルクロリド４．３ｍｇ（０．０２４５ｍｍｏｌ）を加えた後、室温で終夜撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。続いて実施例１５０と同様の操作を行い表題化合物を得た。
収量 １．５８ｍｇ（０．００２１４ｍｍｏｌ） 収率 １１．７％
MS(ESI,m/z)509(MH+)
H-NMR(DMSO-d6)δ1.56-1.71(2H,m),1.84-2.01(2H,m),2.69-2.96(3H,m),3.19-3.28(2H,m),3.42-3.57(1H,m),3.71-3.81(1H,m),3.94-4.02(1H,m),4.04-4.18(1H,m),4.26-4.41(1H,m),6.86(2H,d),7.13(2H,d),7.28-7.81(9H,m),8.12(1H,d),8.14(2H,br),9.01(2H,br),9.29(2H,br)
実施例１５８
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成 ３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩２０ｍｇ（０．０２７１ｍｍｏｌ）、トリエチルアミン２．１８ｍｇ（２．１５ｍｍｏｌ）をエタノール５ｍｌに溶解し、室温でエチルアセトイミダート塩酸塩１０．０ｍｇ（０．０８０９ｍｍｏｌ）を加えた後、室温で終夜撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １３．２ｍｇ（０．００１６９ｍｍｏｌ） 収率 ６２．６％
MS(ESI,m/z)550(MH+)
H-NMR(DMSO-d6)δ1.63-1.82(2H,m),1.97-2.17(2H,m),2.29(3H,s),2.60(1H,dd),2.81(1H,dd),3.42-3.81(5H,m),3.86(2H,d),4.58-4.64(1H,m),6.78(2H,d),7.01(2H,d),7.11-7.68(9H,m),8.09(1H,d),8.58(1H,s),9.04(2H,br),9.11(1H,br),9.27(2H,br)
実施例１５９
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（１−アミジノ−４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩２０ｍｇ（０．０２７１ｍｍｏｌ）、トリエチルアミン７２ｍｇ（２．１５ｍｍｏｌ）をＤＭＦ２ｍｌに溶解し、室温でアミジンスルフィン酸２０．０ｍｇ（０．１８５ｍｍｏｌ）を加えた後、室温で終夜撹拌した。実施例１５０と同様の精製を行い表題化合物を得た。
収量 ８．４ｍｇ（０．０１０８ｍｍｏｌ） 収率 ３９．８％
MS(ESI,m/z)551(MH+)
H-NMR(DMSO-d6)δ1.58-1.68(2H,m),1.89-1.96(2H,m),2.54-2.62(1H,m),2.68-2.97(3H,m),3.21-3.42(2H,m),3.54-3.68(1H,m),3.92(2H,d),4.30-4.41(1H,m),6.73(2H,d),6.92(2H,d),7.05-7.72(9H,m),8.08(1H,d),8.90(4H,br),9.21(4H,br)
実施例１６０
３−［（２Ｓ）−２−（エタンスルフォニルアミノ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成 ３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩１．１９ｇ（１．９９ｍｍｏｌ）を出発原料とし、実施例１５２と同様の操作を行い、得られる中間体を精製することなく、実施例１５８と同様の操作により粗製物を得た。その後実施例１５０と同様の精製を行い表題化合物を得た。
収量 ６３ｍｇ（０．０８６ｍｍｏｌ） 収率 ４．３％
MS(ESI,m/z)502(MH+)
H-NMR(D2O)δ1.05(3H,t),1.82-1.97(2H,m),2.07-2.17(2H,m),2.37(3H,s),2.62-3.21(4H,m),3.47-3.96(5H,m),4.06-4.20(2H,m),4.67-4.73(1H,m),7.18(2H,d),7.29(2H,d),7.30-7.61(4H,m)
実施例１６１
３−［（２Ｓ）−２−（ブタンスルフォニルアミノ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成 ３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩１．１９ｇ（１．９９ｍｍｏｌ）を出発原料とし、実施例１５３と同様の操作を行い、得られる中間体を精製することなく、実施例１５８と同様の操作により粗製物を得た。その後実施例１５０と同様の精製を行い表題化合物を得た。
収量 １１．８ｍｇ（０．２３４ｍｍｏｌ） 収率 １１．８％
MS(ESI,m/z)530(MH+)
H-NMR(DMSO-d6)δ0.89(3H,t),1.10-1.50(4H,m),1.71-1.90(2H,m),1.98-2.12(2H,m),2.28-2.56(2H,q),2.60-2.98(2H,m),3.52-3.60(2H,m),3.62-3.92(3H,m),3.98-4.07(2H,m),4.58-4.69(1H,m),6.92(2H,d),7.21(2H,d),7.24-7.61(4H,m),8.57(1H,br),9.05(1H,br),9.22(2H,br),9.28(2H,br)
実施例１６２
３−［（２Ｓ）−２−（２−ナフタレンスルフォニルアミノ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル 塩酸塩１．１９ｇ（１．９９ｍｍｏｌ）を出発原料とし、実施例１５５と同様の操作を行い、得られる中間体を精製することなく、実施例１５８と同様の操作により粗製物を得た。その後実施例１５０と同様の精製を行い表題化合物を得た。
収量 ３６ｍｇ（０．０４３５ｍｍｏｌ） 収率 ２．２％
MS(ESI,m/z)600(MH+)
H-NMR(DMSO-d6)δ1.60-1.79(2H,m),1.90-2.08(2H,m),2.25(3H,s),2.58-2.92(2H,s),3.41-3.58(2H,m),3.60-3.91(3H,m),3.96(2H,d),4.41-4.57(1H,m),6.67(2H,d),6.98(2H,d),7.04(1H,d),7.15(1H,s),7.34(1H,d),7.41(1H,dd),7.60-7.78(5H,m),7.92(1H,d),7.97(1H,d),8.01(1H,d),8.17(1H,d),8.30(1H,s)
実施例１６３
３−［３−［４−［（３Ｓ）−１−アセトイミドイル−３−ピロリジルオキシ］フェニル］−２−（ベンゼンスルフォニルアミノ）プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成 （３Ｓ）−３−ヒドロキシピロリジン−１−カルボン酸ベンジル、２Ｓ）−２−（ｔ−ブトキシカルボニルアミノ）−３−（４−ヒドロキシフェニル）プロピオン酸メチルを出発原料とし、実施例１５４、次に実施例１５８と順次同様の操作を行い表題化合物を得た。
MS(ESI,m/z)536(MH+)
H-NMR(DMSO-d6)アセトイミドイル部位の幾何異性体Ａ、Ｂの１：１の混合物δ1.90-2.05(2H,m),1.99(3H,s,for A),2.03(3H,s,for B),2.35(1H,dd),2.58(1H,dd),3,15-3.60(6H,m),3.67(2H,m),4.87(1H,d),6.50(2H,dd),6.76(2H,d),6.86(1H,dd),6.96(1H,br),7.10-7.28(4H,m),7.40(2H,d),7.82(1H,d),8.10(1H,s,for A),8.18(1H,s,for A),8.80(1H,s,for B),8.87(1H,s,for B),8.88(2H,s),9.01(2H,s)
実施例１６４
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルメチル）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
工程１
（２Ｓ）−３−［４−［（１−アセチル−４−ピペリジル）ヒドロキシメチル］フェニル］−２−（ベンゼンスルフォニルアミノ）プロパノールの合成
（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−フェニルプロピオン酸メチル６．３２ｇ（１９．８ｍｍｏｌ）、Ｎ−アセチルイソニペコチン酸クロリド３．８８ｇ（２０．４ｍｍｏｌ）をジクロロメタン６０ｍｌに懸濁し、塩化アルミニウム１３．６ｇ（１０２．０ｍｍｏｌ）を加えた後、室温で終夜撹拌した。ジクロロメタンを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。続いてエタノール３０ｍｌとメタノール５０ｍｌの混合溶媒に溶解し水素化ホウ素ナトリウム１．６８ｇ（４４．４ｍｍｏｌ）を加えて終夜撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により表題化合物を得た。
収量 ２．１１ｇ（４．７３ｍｍｏｌ） 収率 ２３．９％
MS(ESI,m/z)469(MNa+)
工程２
４−［４−［（２Ｓ）−３−アセトキシ−２−（ベンゼンスルフォニルアミノ）プロピル］フェニル］メチル］ピペリジンの合成
（２Ｓ）−３−［４−［（１−アセチル−４−ピペリジル）ヒドロキシメチル］フェニル］−２−（ベンゼンスルフォニルアミノ）プロパノール２．１１ｇ（４．７３ｍｍｏｌ）を４Ｎ塩化水素２０ｍｌ、エタノール４０ｍｌに溶解し９５℃で終夜撹拌した。溶媒を留去し得られた残渣に１０％パラジウム炭素１００ｍｇ、濃硫酸０．５ｍｌおよび酢酸２０ｍｌを加え５０℃、４気圧の水素雰囲気下で還元を行った。溶媒を留去して表題の粗製物を得た。
収量 ２９１ｍｇ（０．６７５ｍｍｏｌ） 収率 １４．３％
工程３
４−［４−［（２Ｓ）−３−アセトキシ−２−（ベンゼンスルフォニルアミノ）プロピル］フェニル］メチル］ピペリジン−１−カルボン酸ｔ−ブチルの合成
４−［４−［（２Ｓ）−３−アセトキシ−２−（ベンゼンスルフォニルアミノ）プロピル］フェニル］メチル］ピペリジン２９１ｍｇ（０．６７５ｍｍｏｌ）、ジ−ｔ−ブチルジカーボネート１５１ｍｇ（０．６９３ｍｍｏｌ）、トリエチルアミン７２６ｍｇ（７．１７ｍｍｏｌ）をジクロロメタン２０ｍｌに溶解し終夜撹拌した。溶媒を留去した後、１Ｎ水酸化ナトリウム水溶液０．５ｍｌ、メタノール４０ｍｌを加え４０℃で終夜反応した。溶媒を留去して得られた残渣をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを減圧留去することにより表題化合物を得た。
収量 １６８ｍｇ（０．３４４ｍｍｏｌ） 収率 ５１．０％
MS(ESI,m/z)489(MH+)
工程４
４−［４−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−メタンスルフォニルオキシプロピル］フェニル］メチル］ピペリジン−１−カルボン酸ｔ−ブチルの合成
４−［４−［（２Ｓ）−３−アセトキシ−２−（ベンゼンスルフォニルアミノ）プロピル］フェニル］メチル］ピペリジン−１−カルボン酸ｔ−ブチル１６８ｍｇ（０．３４４ｍｍｏｌ）、トリエチルアミン５００ｍｇ（４．９４ｍｍｏｌ）をジクロロメタン１５ｍｌに溶解し氷冷化、メタンスルホニルクロリド１００ｍｇ（０．８７３ｍｍｏｌ）し３時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により表題の粗製物を得た。
収量 １３９ｍｇ（０．２４５ｍｍｏｌ） 収率 ７１．２％
MS(ESI,m/z)567(MH+)
H-NMR(CDCl3)δ1.03-1.90(5H,m),1.42(9H,s),2.43(2H,d),2.60-2.84(2H,m),3.15(3H,s),3.60-3.71(1H,m),3.98-4.21(6H,m),6.92(2H,d),6.97(2H,d),7.41-7.77(5H,m)
工程５
４−［［４−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−クロロプロピル］フェニル］メチル］ピペリジン−１−カルボン酸ｔ−ブチルの合成
４−［４−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−メタンスルフォニルオキシプロピル］フェニル］メチル］ピペリジン−１−カルボン酸ｔ−ブチル１３９ｍｇ（０．２４５ｍｍｏｌ）、塩化リチウム５００ｍｇ（１１．７ｍｍｏｌ）をＤＭＦ１５ｍｌに溶解し５０℃で６時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により表題の粗製物を得た。
収量 ９４．８ｍｇ（０．１８７ｍｍｏｌ） 収率 ７６．３％
MS(ESI,m/z)508(MH+)
H-NMR(CDCl3)δ1.03-1.80(5H,m),1.42(9H,s),2.45(2H,d),2.60-2.84(2H,m),3.10(3H,s),3.47(2H,d),3.64-3.80(1H,m),4.01-4.18(4H,m),6.94-7.00(4H,m),7.40-7.82(5H,m)
工程６
３−［２−（ベンゼンスルフォンアミノ）−３−［４−［［１−（ｔ−ブトキシカルボニルアミノ）ピペリジル］メチル］フェニル］プロポキシ］ベンスアミジンの合成
４−［［４−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−クロロプロピル］フェニル］メチル］ピペリジン−１−カルボン酸ｔ−ブチル９４．８ｍｇ（０．１８７ｍｍｏｌ）、３−シアノフェノール２７５ｍｇ（２．３１ｍｍｏｌ）および炭酸カリウム３８５ｍｇ（２．７９ｍｍｏｌ）をＤＭＦ１５ｍｌに溶解し７５℃で６０時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により得られた油状残渣に対し実施例１５０と同様の操作を行い表題化合物を得た。
収量 ８７．５ｍｇ（０．０１４８ｍｍｏｌ） 収率 ７９．１％
MS(ESI,m/z)590(MH+)
H-NMR(CDCl3)δ1.03-1.79(5H,m),1.42(9H,s),2.24(2H,d),2.48-2.92(2H,m),3.68-3.91(2H,m),3.92(2H,d),3.98-4.10(2H,m),4.27-4.38(1H,m),6.91(2H,d),6.98(2H,d),7.28-7.91(9H,m)
工程７
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルメチル）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［２−（ベンゼンスルフォンアミノ）−３−［４−［［１−（ｔ−ブトキシカルボニルアミノ）ピペリジル］メチル］フェニル］プロポキシ］ベンスアミジン４３．８ｍｇ（０．０７４３ｍｍｏｌ）を用い実施例１５０と同様操作を行い表題化合物を得た。
収量 ３．６ｍｇ（０．００４９０ｍｍｏｌ） 収率 ６．６％
MS(ESI,m/z)507(MH+)
H-NMR(DMSO-d6)δ1.18-1.31(2H,m),1.59-1.81(3H,m),2.41(2H,d),2.55-2.87(4H,m),3.10-3.22(2H,m),3.51-3.68(1H,m),3.86(2H,d),6.87-6.96(4H,m),7.03(1H,dd),7.17(1H,d),7.28-7.51(4H,m),7.58-7.65(2H,m),8.04(1H,d),8.18(1H,br),8.47(1H,br),9.05(2H,br),9.21(2H,br)
実施例１６５
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−［（１−アセトイミドイル−４−ピペリジル）メチル］フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩の合成 ３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルメチル）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩６．８ｍｍｏｌ（０．００９４ｍｍｏｌ）を用い実施例１５８と同様の操作を行い表題化合物を得た。
収量 １．７ｍｇ（０．００２１９ｍｍｏｌ） 収率 ２３．４％
MS(ESI,m/z)548(MH+)
H-NMR(DMSO-d6)δ1.10-1.28(2H,m),1.60-1.73(2H,m),1.77-1.91(1H,m),2.22(3H,s),1 44(2H,d),2.63(1H,dd),2.84(1H,dd),3.01-3.28(2H,m),3.58-3.67(1H,m),3.82-4.01(2H,m),3.92(2H,d),6.98(2H,d),6.99(2H,d),7.11(1H,dd),7.21(1H,d),7.35-7.56(4H,m),7.61-7.71(2H,m),8.09(1H,d),8.45(1H,br),9.00(2H,br),9.27(2H,br)
実施例１６６
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸 二トリフルオロ酢酸塩の合成
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸エチル 二トリフルオロ酢酸塩の合成
工程１
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（４−ヨードベンゼンスルフォニルアミノ）プロポキシ］ベンゾニトリルの合成 ３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］ベンゾニトリル２．５４ｇ（４．３４ｍｍｏｌ）に、４規定塩化水素のジオキサン溶液２５ｍｌ、ジオキサン１２．５ｍｌを加えた。室温で２４時間撹拌後、溶媒を減圧留去して得た残渣をＤＭＦ４０ｍｌに溶解した。ジイソプロピルエチルアミン１．７７ｍｌ（１３．０ｍｍｏｌ）、４−ヨードベンゼンスルフォニルクロリド１．９７ｇ（６．５１ｍｍｏｌ）を０℃で加えた。３０分後、室温に戻して１９時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２．５０ｇ（３．３９ｍｍｏｌ） 収率 ７８％
H-NMR(CDCl3)δ1.62-1.83(2H,m),1.63-2.00(2H,m),2.62-2.80(1H,m),2.83-3.00(1H,m),3.40-3.53(2H,m),3.62-3.80(3H,m),3.81-4.00(2H,m),4.40-4.45(1H,m),4.40-4.45(1H,m),5.14(2H,s),5.20-5.36(1H,m),6.73(2H,d),6.90(2H,d),7.01(2H,d),7.24-7.44(9H,m),7.70(2H,d)
工程２
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（３−シアノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸エチルの合成
３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（４−ヨードベンゼンスルフォニルアミノ）プロポキシ］ベンゾニトリル７３８ｍｇ（１．００ｍｍｏｌ）をアセトニトリル５ｍｌに溶解し、アクリル酸エチル０．２２ｍｌ（２．０ｍｍｏｌ）、酢酸パラジウム１１ｍｇ（０．０５ｍｍｏｌ）、トリス−ｏ−トリルホスフィン９１ｍｇ（０．３ｍｍｏｌ）、トリブチルアミン０．４８ｍｌ（２．０ｍｍｏｌ）を加え１５時間加熱還流した。ジクロロメタンを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ５４４ｍｇ（０．７５ｍｍｏｌ） 収率 ７５％
H-NMR(CDCl3)δ0.93(3H,s),1.64-1.83(2H,m),1.85-2.00(2H,m)2.70-3.00(2H,m),3.40-3.52(1H,m),3.66-3.80(3H,m),3.82-4.28(2H,q),4.36-4.44(1H,m),5.14(2H,s),6.50(1H,d),6.72(2H,d),6.92(2H,d),7.28-7.40(7H,m),7.52(2H,d),6.99-7.04(2H,m),7.73(2H,d)
工程３
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸 二トリフルオロ酢酸塩の合成
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸エチル 二トリフルオロ酢酸塩の合成
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（３−シアノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸エチルを４規定塩化水素のジオキサン溶液４．５ｍｌに溶解し、塩化水素を３０％含有する（Ｗ／Ｖ）エタノール０．５ｍｌを加えた。室温で９６時間撹拌後、溶媒を減圧留去して得た残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液２４ｍｌに溶解して室温で２４時間撹拌した。溶媒を留去して得られた残留物を０℃で２０％臭化水素を含む酢酸１８ｍｌを加え１時間撹拌後、室温に戻して７時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸 二トリフルオロ酢酸塩：
収量 ８８ｍｇ（０．１１ｍｍｏｌ） 収率 １４％
MS(ESI,m/z)579(MH+)
H-NMR(DMSO-d6))δ1.70-1.85(2H,m),1.98-2.12(2H,m),2.55-2.65(1H,m),2.78-2.88(1H,m),3.00-3.16(2H,m),3.18-3.30(2H,m),3.57-3.70(1H,m),3.95-4.00(2H,m),4.53(1H,m),6.60(1H,d),6.72(2H,d),6.99(2H,d),7.15(1H,dd),7.29(1H,d),7.39(1H,d),7.54(1H,t),7.57(2H,d),7.59(1H,d),7.67(2H,d),8.18(1H,d),8.60(2H,br),9.20(2H,br),9.38(2H,br)
２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸エチル 二トリフルオロ酢酸塩：
収量 １４９ｍｇ（０．１８ｍｍｏｌ） 収率 ２３％
MS(ESI,m/z)607(MH+)
H-NMR(DMSO-d6))δ1.70-1.85(2H,m),1.98-2.12(2H,m),2.55-2.65(1H,m),2.78-2.88(1H,m),3.00-3.16(2H,m),3.18-3.30(2H,m),3.57-3.70(1H,m),3.95-4.00(2H,m),4.53(1H,m),6.60(1H,d),6.72(2H,d),6.99(2H,d),7.15(1H,dd),7.29(1H,d),7.39(1H,d),7.54(1H,t),7.57(2H,d),7.59(1H,d),7.67(2H,d),8.18(1H,d),8.60(2H,br),9.20(2H,br),9.38(2H,br)
実施例１６７
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸メチル 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸エチル 二トリフルオロ酢酸塩の合成
工程１
４−［（２Ｓ）−１−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（３−シアノフェノキシ）−２−プロピルスルファモイル］安息香酸メチルの合成 ３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（４−ヨードベンゼンスルフォニルアミノ）プロポキシ］ベンゾニトリル７３８ｍｇ（１．００ｍｍｏｌ）をジメチルホルムアミド５ｍｌに溶解し、酢酸パラジウム１１ｍｇ（０．０５ｍｍｏｌ）、メタノール０．８１ｍｌ（２．０ｍｍｏｌ）、トリエチルアミン０．２８ｍｌ（２．０ｍｍｏｌ）を加え一酸化炭素存在下３．５時間７０℃で加熱した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ５１８ｍｇ（０．７６ｍｍｏｌ） 収率 ７６％
工程２
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸メチル 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸エチル 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（３−シアノフェノキシ）−２−プロピルスルファモイル］安息香酸メチル５１８ｍｇ（０．７６ｍｍｏｌ）を出発原料とし、実施例９５の工程５と同様の操作に従って変換した後、脱保護し、表題化合物を得た。
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩：
収量 １７ｍｇ（０．０２ｍｍｏｌ） 収率 ３％
MS(FAB,m/z)553(MH+)
H-NMR(DMSO-d6)δ1.70-1.85(2H,m),2.00-2.15(2H,m),2.53-2.66(1H,m),2.80-2.90(1H,m),3.00-3.16(2H,m),3.20-3.30(2H,m),3.60-3.72(1H,m),3.98-4.03(2H,m),4.53(1H,m),6.72(2H,d),6.99(2H,d),7.18(1H,dd),7.29(1H,d),7.39(1H,d),7.50(1H,t),7.65(2H,d),7.89(2H,d),8.28(1H,d),8.50(2H,br),9.05(2H,br),9.28(2H,br)
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸メチル 二トリフルオロ酢酸塩：
収量 ８０ｍｇ（０．１０ｍｍｏｌ） 収率 １３％
MS(FAB,m/z)567(MH+)
H-NMR(DMSO-d6)δ1.35(3H,t),1.70-1.85(2H,m),2.00-2.15(2H,m),2.55-2.68(1H,m),2.80-2.90(1H,m),3.00-3.16(2H,m),3.20-3.28(2H,m),3.60-3.72(1H,m),3.96-4.00(2H,m),4.34(2H,q),4.53(1H,m),6.75(2H,d),7.02(2H,d),7.15(1H,dd),7.20(1H,d),7.37(1H,d),7.48(1H,t),7.69(2H,d),7.91(2H,d),8.30(1H,d),8.53(2H,br),9.15(2H,br),9.26(2H,br)
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸エチル 二トリフルオロ酢酸塩：
収量 ５１ｍｇ（０．０６ｍｍｏｌ） 収率 ８％
MS(FAB,m/z)581(MH+)
H-NMR(DMSO-d6)δ1.70-1.85(2H,m),2.00-2.15(2H,m),2.53-2.66(1H,m),2.80-2.90(1H,m),3.00-3.16(2H,m),3.20-3.30(2H,m),3.60-3.72(1H,m),3.98-4.03(2H,m),4.53(1H,m),6.72(2H,d),6.99(2H,d),7.18(1H,dd),7.29(1H,d),7.39(1H,d),7.50(1H,t),7.65(2H,d),7.89(2H,d),8.28(1H,d),8.50(2H,br),9.05(2H,br),9.28(2H,br)
実施例１６８
４−［（２Ｓ）−１−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩８ｍｇ（０．０１ｍｍｏｌ）をエタノール２ｍｌに溶解し、エチルアセトイミダート塩酸塩９ｍｇ（０．０７ｍｍｏｌ）、トリエチルアミン０．５ｍｌを加え、２４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ３ｍｇ（０．００３７ｍｍｏｌ） 収率 ３６％
MS(ESI,m/z)594(MH+)
H-NMR(DMSO-d6)δ1.60-1.80(2H,m),1.97-2.10(2H,m),2.29(3H,s),2.54-2.65(1H,m),2.69-2.90(1H,m),3.43-3.60(2H,m),3.62-3.84(3H,m),3.93-4.10(2H,m),4.55(1H,m),6.72(2H,d),6.99(2H,d),7.17(1H,dd),7.29(1H,d),7.39(1H,d),7.50(1H,t),7.65(2H,d),7.90(2H,d),8.27(1H,d),8.54-8.60(1H,m),9.03(2H,br),9.12(1H,br),9.28(2H,br)
実施例１６９
４−［（２Ｓ）−１−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸メチル 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸メチル 二トリフルオロ酢酸塩４０ｍｇ（０．０５ｍｍｏｌ）を出発原料とし、実施例１６８と同様の操作に従って表題化合物を得た。
収量 ２０ｍｇ（０．０２４ｍｍｏｌ） 収率 ４８％
MS(ESI,m/z)608(MH+)
H-NMR(DMSO-d6)δ1.62-1.82(2H,m),1.98-2.12(2H,m),2.30(3H,s),2.58-2.65(1H,m),2.80-2.87(1H,m),3.20-3.40(2H,m),3.42-3.80(3H,m),3.89(3H,s),3.96-4.05(2H,m),4.53(1H,m),6.78(2H,d),7.02(2H,d),7.18(1H,dd),7.20(1H,d),7.39(1H,d),7.45(1H,t),7.70(2H,d),7.92(2H,d),8.32(1H,d),8.60-8.70(1H,m),9.16(1H,br),9.26(2H,br),9.32(2H,br)
実施例１７０
４−［（２Ｓ）−１−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸エチル 二トリフルオロ酢酸塩の合成
４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸エチル 二トリフルオロ酢酸塩２６ｍｇ（０．０３２ｍｍｏｌ）を出発原料とし、実施例１６８と同様の操作に従って表題化合物を得た。
収量 １０ｍｇ（０．０１２ｍｍｏｌ） 収率 ３７％
MS(ESI,m/z)622(MH+)
H-NMR(DMSO-d6)δ1.34(3H,s),1.55-1.70(2H,m),2.00-2.10(2H,m),2.29(3H,s),2.55-2.68(1H,m),2.77-2.88(1H,m),3.45-3.60(2H,m),3.66-3.80(3H,m),3.95-4.00(2H,m),4.34(2H,q),4.53(1H,m),6.74(2H,d),7.01(2H,d),7.14(1H,dd),7.21(1H,d),7.38(1H,d),7.48(1H,t),7.69(2H,d),7.92(2H,d),8.29(1H,d),8.54-8.58(1H,m),8.99(2H,br),9.10(1H,br),9.26(2H,br)
実施例１７１
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸 二トリフルオロ酢酸塩の合成
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸 二トリフルオロ酢酸塩３９ｍｇ（０．０４７ｍｍｏｌ）を出発原料とし、実施例１６８と同様の操作に従って表題化合物を得た。
収量 ２０ｍｇ（０．０１２ｍｍｏｌ） 収率 ４９％
MS(FAB,m/z)620(MH+)
H-NMR(DMSO-d6)δ1.60-1.80(2H,m),1.95-2.10(2H,m),2.28(3H,s),2.54-2.65(1H,m),2.77-2.88(1H,m),3.45-3.60(2H,m),3.60-3.80(3H,m),3.91-4.03(2H,m),4.53(1H,m),6.60(1H,d),6.72(2H,d),6.98(2H,d),7.15(1H,dd),7.29(1H,d),7.39(1H,d),7.50(1H,t),7.56(2H,d),7.63(1H,d),7.67(2H,d),8.18(1H,d),8.55-8.60(1H,m),9.07(2H,br),9.13(1H,br),9.28(2H,br)
実施例１７２
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸エチル 二トリフルオロ酢酸塩の合成
（２Ｅ）−３−［４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］フェニル］アクリル酸エチル 二トリフルオロ酢酸塩７２ｍｇ（０．０８６ｍｍｏｌ）を出発原料とし、実施例１６８と同様の操作に従って表題化合物を得た。
収量 ４０ｍｇ（０．０４６ｍｍｏｌ） 収率 ５３％
MS(FAB,m/z)648(MH+)
H-NMR(DMSO-d6)δ1.29(3H,t),1.60-1.80(2H,m),1.96-2.10(2H,m),2.28(3H,s),2.54-2.65(1H,m),2.78-2.88(1H,m),3.45-3.56(2H,m),3.60-3.80(3H,m),3.95-4.02(2H,m),4.22(2H,q),4.53(1H,m),6.68(1H,d),6.72(2H,d),6.98(2H,d),7.17(1H,dd),7.27(1H,d),7.38(1H,d),7.50(1H,t),7.56(2H,d),7.64(1H,d),7.67(2H,d),8.18(1H,d),8.50-8.60(1H,m),9.03(2H,br),9.10(1H,br),9.27(2H,br)
実施例１７３
２−［（２Ｓ）−１−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
工程１
２−［（２Ｓ）−１−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（３−シアノフェノキシ）−２−プロピルスルファモイル］安息香酸ベンジルの合成 ３−［（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（４−ヨードベンゼンスルフォニルアミノ）プロポキシ］ベンゾニトリル５００ｍｇ（０．８５４ｍｍｏｌ）に、４規定塩化水素のジオキサン溶液５ｍｌ、ジオキサン２．５ｍｌを加えた。室温で２４時間撹拌後、溶媒を減圧留去して得た残渣をＤＭＦ８ｍｌに溶解し、ジイソプロピルエチルアミン０．４９ｍｌ（２．５６ｍｍｏｌ）、２−（ベンジルオキシカルボニル）ベンゼンスルフォニルクロリド３９８ｍｇ（１．２８ｍｍｏｌ）を０℃で加えた。１時間撹拌した後、室温に戻して更に２４時間撹拌した。反応液を酢酸エチルで抽出し、水、１Ｎ塩化水素、飽和食塩水で洗浄し、粉末硫酸マグネシウムで乾燥させた。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、表題化合物を得た。
収量 ４９０ｍｇ（０．６４６ｍｍｏｌ） 収率 ７７％
H-NMR(CDCl3)δ1.63-1.80(2H,m),1.82-2.00(2H,m),2.70-3.00(2H,m),3.38-3.49(2H,m),3.61-3.93(4H,m),4.22-4.45(2H,m),5.15(2H,s),5.37(2H,m),6.38(1H,d),6.55(1H,d),6.78(1H,d),6.83(1H,t),6.93(1H,d),7.00(1H,d),7.20-7.60(13H,m),7.71(1H,d),7.82(1H,d)
工程２
２−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
２−［（２Ｓ）−１−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（３−シアノフェノキシ）−２−プロピルスルファモイル］安息香酸ベンジル４９０ｍｇ（０．６４６ｍｍｏｌ）を出発原料として用い、実施例９５の工程５と同様の操作により変換を行った後、脱保護し、表題化合物を得た。
収量 ５０ｍｇ（０．０４６ｍｍｏｌ） 収率 １０％
MS(FAB,m/z)552(M+)
H-NMR(DMSO-d6)δ1.70-1.85(2H,m),2.00-2.12(2H,m),2.60-2.62(1H,m),2.77-2.88(1H,m),3.01-3.16(2H,m),3.19-3.27(2H,m),3.78-3.94(2H,m),4.46-4.59(2H,m),6.77(2H,d),7.02(2H,d),7.09(2H,d),7.22(1H,d),7.31(1H,d),7.38(1H,t),7.49(1H,dd),7.58(1H,d),7.73(1H,br),7.80(1H,d),8.15(1H,br),8.42-8.58(1H,m),9.07(1H,br),9.27(1H,br)
工程３
２−［（２Ｓ）−１−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩の合成
２−［Ｎ−［（１S）−１−［（３−アミジノ−１−フェニル）オキシ］メチル−２−［４−（４−ピペリジル）オキシ］フェニル］エチル］スルファモイル安息香酸二トリフルオロ酢酸塩５０ｍｇ（０．０４６ｍｍｏｌ）を出発原料として用い、実施例１６８と同様の操作に従って表題化合物を得た。
収量 ２５ｍｇ（０．０３０ｍｍｏｌ） 収率 ６６％
MS(FAB,m/z)593(M+)
H-NMR(DMSO-d6)δ1.65-1.80(2H,m),1.95-2.10(2H,m),2.28(3H,s),2.59-2.70(1H,m),2.73-2.88(1H,m),3.44-3.58(2H,m),3.67-3.80(2H,m),3.82-3.94(3H,m),4.62(1H,m),6.77(2H,d),7.00(2H,d),7.10(1H,dd),7.21(1H,d),7.37(1H,t),7.42(1H,d),7.49(1H,d),7.58(1H,d),7.73(1H,br),7.75(1H,d),8.15(1H,d),8.57(1H,br),9.03(2H,br),9.12(1H,br),9.26(2H,br)
実施例１７４
３−［（３Ｒ）−３−（ベンゼンスルフォニルアミノ）−４−［４−（４−ピペリジルオキシ）フェニル］ブチル］ベンズアミジン 二トリフルオロ酢酸塩の合成
工程１
３−［（３Ｓ）−４−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（ｔ−ベトキシカルボニルアミノ）−１−ブテニル］ベンゾニトリルの合成 （２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロピオン酸メチル３．８７ｇ（７．７０ｍｍｏｌ）をトルエン７７ｍｌに溶解し、−７８℃で水素化ジイソブチルアルミニウムの１．０Ｍヘキサン溶液１９．３ｍｌ（１９．３ｍｍｏｌ）を加え１０分間撹拌した。ここにメタノール１０ｍｌ、酒石酸ナトリウムカリウムの飽和水溶液２０ｍｌを加え室温で更に１時間撹拌する。酢酸エチルを抽出溶媒とし常法に従って処理し油状残渣を得た。こうして得られた油状残渣をエタノール３０ｍｌ、テトラヒドロフラン３０ｍｌの混合溶媒に溶解し（３−シアノベンジル）トリフェニルホスフォニウム ブロミド３．５３ｇ（７．７０ｍｍｏｌ）、ＤＢＵ１．１５ｍｌ（７．７０ｍｍｏｌ）を室温で加え１時間撹拌した。溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトクラフィーで精製し表題化合物を幾何異性体の混合物（Ｅ：Ｚ＝２：３）として得た。
収量 ２．３３ｇ（４．００ｍｍｏｌ） 収率 ５２％
MS(ESI,m/z)604(MNa+)
H-NMR(CDCl3)δ1.43(9H,s),1.69-1.83(2H,m),1.85-1.98(2H,m),2.68(1H,dd),2.89(1H,dd),3.46(2H,ddd),3.76(2H,ddd),4.42-4.50(1H,m),4.52-4.67(1H,m),5.14(2H,s),5.5g(1H,dd,for Z isomer),6.20(1H,dd,for E isomer),6.41(1H,d,for E isomer),6.42(1H,d,for Z isomer),6.81(1H,d,for Z isomer),6.85(1H,d,for E isomer),7.03(1H,d,for Z isomer),7.11(1H,d,for E isomer),7.28-7.50(9H,m)
工程２
３−［（３Ｓ）−４−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（ベンゼンスルフォニルアミノ）−１−ブテニル］ベンゾニトリルの合成
３−［（３Ｓ）−４−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（ｔ−ベトキシカルボニルアミノ）−１−ブテニル］ベンゾニトリル２．３３ｇ（４．００ｍｍｏｌ）を４規定塩化水素ジオキサン溶液２０ｍｌ、ジオキサン１０ｍｌに溶解し室温で２４時間撹拌した。溶媒を減圧留去し油状残渣を得た。こうして得られた油状残渣をＤＭＦ２０ｍｌに溶解し、ジイソプロピルエチルアミン２．０９ｍｌ（１２．００ｍｍｏｌ）、ベンゼンスルフォニルクロリド１．０６ｇ（６．００ｍｍｏｌ）を０℃で加え、２．５時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を幾何異性体の混合物（Ｅ：Ｚ＝２：３）として得た。
収量 ２．１１ｇ（３．３９ｍｍｏｌ） 収率 ８５％
H-NMR(CDCl3)δ1.70-1.83(2H,m),1.86-2.01(2H,m),2.73(1H,dd,for Z isomer),2.81(1H,d,for E isomer),2.86(1H,dd,for Z isomer),2.98(1H,d,for E isomer),3.45(2H,ddd),3.76(2H,ddd),4.11-4.22(1H,m),4.43-4.49(1H,m),5.14(2H,s),5.52(1H,dd,for Z isomer),5.94(1H,dd,for E isomer),6.27(1H,d,for E isomer),6.34(1H,d,for Z isomer),6.77(2H,d),6.90(2H,d),7.08(1H,d),7.26-7.38(9H,m),7.49(1H,t),7.56(1H,d)
工程３
３−［（３Ｒ）−３−（ベンゼンスルフォニルアミノ）−４−［４−（４−ピペリジルオキシ）フェニル］ブチル］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（３Ｓ）−４−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（ベンゼンスルフォニルアミノ）−１−ブテニル］ベンゾニトリル６６９ｍｇ（１．０８ｍｍｏｌ）、１０％パラジウム炭素２０ｍｇをメタノール２ｍｌ、ジクロロメタン３ｍｌの混合溶媒に溶解し、１気圧の水素雰囲気下、室温で２時間撹拌した。吸引濾過によりパラジウム炭素を除き、濾液を濃縮して油状残渣を得た。こうして得られた油状残渣を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール１０ｍｌに加え、室温で一晩撹拌した。溶媒を留去して得られた残留物を室温でアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液３０ｍｌに溶解して室温で一晩撹拌した。溶媒を留去して得られた残留物を臭化水素の酢酸溶液２０ｍｌに溶解し室温で２時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ０．３０２ｇ（０．４１ｍｍｏｌ） 収率 ３８％
H-NMR(DMSO-d6)δ1.50-1.70(2H,m),1.70-1.86(2H,m),2.00-2.11(2H,m),2.33-2.74(4H,m),3.01-3.16(2H,m),3.18-3.30(2H,m),3.31-3.44(1H,m),4.51-4.60(1H,m),6.81(2H,d),6.96(2H,d),7.33(1H,d),7.43-7.62(5H,m),7.74(2H,d),7.80(1H,d),8.53(2H,br),9.08(2H,s),9.22(2H,s)
実施例１７５
３−［（３Ｒ）−３−（ベンゼンスルフォニルアミノ）−４−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］ブチル］ベンズアミジン 二トリフルオロ酢酸の合成
３−［（３Ｒ）−３−（ベンゼンスルフォニルアミノ）−４−［４−（４−ピペリジルオキシ）フェニル］ブチル］ベンズアミジン 二トリフルオロ酢酸塩１０．７ｍｇ（０．０１５ｍｍｏｌ）を出発原料とし、実施例１５８と同様の操作に従い表題化合物を得た。
収量 １１．１ｍｇ（０．０１４ｍｍｏｌ） 収率 ９５％
MS(ESI,m/z)548(MH+)
H-NMR(DMSO-d6)δ1.50-1.82(4H,m),1.97-2.10(2H,m),2.29(3H,s),2.34-2.72(4H,m),3.22-3.59(4H,m),3.68-3.82(1H,m),4.57-4.66(1H,m),6.82(2H,d),6,97(2H,d),7.33(1H,d),7.43-7.62(5H,m),7.74(2H,d),7.81(1H,d),8.60(1H,s),9.15(1H,s),9.20(2H,s),9.23(2H,s)
実施例１７６
３−［（３Ｓ，１Ｚ）−３−（ベンゼンスルフォニルアミノ）−４−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−１−ブテニル］ベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（３Ｓ）−４−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−３−（ベンゼンスルフォニルアミノ）−１−ブテニル］ベンゾニトリル１２０ｍｇ（０．１９ｍｍｏｌ）を塩化水素を３０％含有する（Ｗ／Ｖ）エタノール２ｍｌに加え、室温で一晩撹拌した。続いて室温でアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液５ｍｌに溶解して室温で一晩撹拌した。溶媒を留去して得られた残留物を氷冷下、臭化水素の酢酸溶液５ｍｌに溶解し２時間撹拌した。溶媒を留去して得られた残留物を実施例１５８と同様の操作に従って変換し、表題化合物を得た。
収量 １２ｍｇ（０．０１６ｍｍｏｌ） 収率 ８．４％
MS(ESI,m/z)546(MH+)
H-NMR(DMSO-d6)δ1.64-1.81(2H,m),1.96-2.10(2H,m),2.28(3H,s),2.46-2.52(1H,m),2.67-2.73(1H,m),3.47-3.52(2H,m),3.70-3.77(2H,m),4.11-4.23(1H,m),4.56-4.67(m,1H),5.47(1H,dd),6.27(1H,d),6.82(2H,d),6.96(2H,d),7.06(1H,d),7.28(1H,s),7.42-7.49(3H,m),7.54-7.58(3H,m),7.65(1H,d),8.02(1H,d),8.58(1H,s),9.12(1H,s),9.18(2H,s),9.29(2H,s)
実施例１７７
（２Ｓ）−Ｎ−（３−アミジノフェニル）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロピオンアミド 二トリフルオロ酢酸塩の合成
工程１
（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロピオン酸メチルの合成
（２Ｓ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロピオン酸メチル３．９６ｇ（７．９４ｍｍｏｌ）を４規定塩化水素のジオキサン溶液３０ｍｌに溶解し、室温で４時間撹拌した。溶媒を留去し得られた油状残渣をＤＭＦ４０ｍｌに溶解し、０℃でジイソプロピルエチルアミン５．１４ｍｌ（２３．８３ｍｍｏｌ）、ベンゼンスルフォニウムクロリド２．１０ｇ（１１．９１ｍｍｏｌ）を加え室温で２．５時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ３．５ｇ（６．５２ｍｍｏｌ） 収率 ８２％
H-NMR(CDCl3)δ1.60-2.00(4H,m),2.95(1H,d),3.45(2H,ddd),3.47(3H,s),3.76(2H,ddd),4.19(1H,dt),4.41-4.49(1H,m),5.16(2H,s),6.78(2H,d),6.98(2H,d),7.30-7.58(8H,m),7.76(2H,d)
工程２
（２Ｓ）−Ｎ−（３−アミジノフェニル）−２−（ベンゼンスルフォニルアミノ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロピオンアミドの合成 （２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロピオン酸メチル１．７５ｇ（３．２６ｍｍｏｌ）をメタノール１０ｍｌ、テトラヒドロフラン１０ｍｌの混合溶媒に溶解し、１規定水酸化ナトリウム水溶液６．５２ｍｌ（６．５２ｍｍｏｌ）を加え、５０℃で一晩撹拌した。エーテルで洗浄した後、濃塩酸を加えて酸性とし、ジクロロメタンを抽出溶媒とし、実施例１の工程１と同様の単離操作により油状残渣を得た。こうして得られた油状残渣をピリジン６０ｍｌに溶解し、３−アミノベンズアミジン 二塩酸塩７４７ｍｇ（３．６１ｍｍｏｌ）、ＷＳＣ７５０ｍｇ（３．９２ｍｍｏｌ）を加え、室温で一晩撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．８９ｇ（２．９０ｍｍｏｌ） 収率 ８９％
H-NMR(CDCl3)δ1.72-1.83(2H,m),1.85-2.00(2H,m),3.32(1H,dd),3.44(2H,ddd),3.61(1H,dd),3.78(2H,ddd),4.04-4.14(1H,m),4.42-4.51(1H,m),5.32(2H,s),6.84(2H,d),7.18(2H,d),7.28-7.38(9H,m),7.43-7.50(2H,m),7.64-7.69(2H,m),7.77-7.83(1H,m),8.02(4H,s)
工程３
（２Ｓ）−Ｎ−（３−アミジノフェニル）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロピオンアミド 二トリフルオロ酢酸塩の合成
（２Ｓ）−Ｎ−（３−アミジノフェニル）−２−（ベンゼンスルフォニルアミノ）−３−［４−［１−（ベンジルオキシカルボニル）−４−ピペリジルオキシ］フェニル］プロピオンアミド９０ｍｇ（０．１３ｍｍｏｌ）を臭化水素の酢酸溶液２０ｍｌに溶解し室温で２時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。収量 ３４ｍｇ（０．０６５ｍｍｏｌ） 収率 ４９％
MS(ESI,m/z)522(MH+)
H-NMR(DMSO-d6)δ1.71-1.88(2H,m),2.02-2.16(2H,m),2.68(1H,dd),2.88(1H,dd),3.03-3.17(2H,m),3.20-3.30(2H,m),4.05-4.15(1H,m),4.54-4.62(1H,m),6.83(2H,d),7.10(2H,d),7.34(2H,dt),7.42-7.50(2H,m),7.57(2H,d),7.70(1H,d),7.92(1H,d),8.38(1H,d),8.58(2H,br),9.13(2H,s),9.31(2H,s),10.42(1H,s)
実施例１７８
（２Ｓ）−Ｎ−（３−アミジノフェニル）−２−（ベンゼンスルフォニルアミノ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］プロピオンアミド 二トリフルオロ酢酸塩の合成
（２Ｓ）−Ｎ−（３−アミジノフェニル）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロピオンアミド 二トリフルオロ酢酸塩８０ｍｇ（０．１５３ｍｍｏｌ）を出発原料とし、実施例１５８と同様の操作に従い表題化合物を得た。
収量 ３０ｍｇ（０．０３８ｍｍｏｌ） 収率 ２５％
MS(ESI,m/z)563(MH+)
H-NMR(DMSO-d6)δ1.65-1.72(2H,m),1.98-2.12(2H,m),2.30(3H,s),2.67(1H,dd),2.88(1H,dd),3.46-3.60(2H,m),3.69-3.82(2H,m),4.04-4.16(1H,m),4.58-4.68(1H,m),6.82(2H,d),7.11(2H,d),7.33(2H,t),7.42-7.48(2H,m),7.53(2H,t),7.70(1H,d),7.92(1H,s),8.38(1H,d),8.60(1H,s),9.11(2H,s),9.12(1H,s),9.32(2H,s),10.41(1H,s)
実施例１７９
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］−４−ヨードベンズアミジン 二トリフルオロ酢酸塩の合成
工程１
３−［（２Ｓ）−３−［４−（１−ベンジルオキシカルボニル−４−ピペリジルオキシ）フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］−４−ヨードベンゾニトリルの合成 ４−［４−［（２Ｓ）−３−クロロ−２−（ｔ−ブトキシカルボニルアミノ）プロピル］フェノキシ］ピペリジン−１−カルボン酸ベンジル１．３ｇ（２．６ｍｍｏｌ）、３-ヒドロキシ-４-ヨードベンゾ ニトリル６８６ｍｇ（２．８ｍｍｏｌ）、炭酸カリウム３９０ｍｇ（２．８ｍｍｏｌ）をジメチルホルムアミドに溶解し、６５℃で４日間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。このものは精製することなく次の反応に用いた。
工程２
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（１−ベンジルオキシカルボニル−４−ピペリジルオキシ）フェニル］プロポキシ］−４−ヨードベンゾニトリルの合成 ３−［（２Ｓ）−３−［４−（１−ベンジルオキシカルボニル−４−ピペリジルオキシ）フェニル］−２−（ｔ−ブトキシカルボニルアミノ）プロポキシ］−４−ヨードベンゾニトリル１．６ｇ（２．７ｍｍｏｌ）を４規定塩化水素のジオキサン溶液に溶解し、室温で一晩撹拌した。溶媒を留去し、残留物をジメチルホルムアミドに溶解し、氷冷下Ｎ，Ｎ−ジイソブチルエチルアミン１ｍｌ（６ｍｍｏｌ）、ベンゼンスルホニルクロリド０．３４ｍｌ（２．７ｍｍｏｌ）を加え、２時間撹拌した。酢酸エチルを抽出溶媒とし、実施例１の工程１と同様の単離操作により粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 １．１７ｇ（１．５６ｍｍｏｌ） 収率 ７１％
H-NMR(CDCl3)δ1.70-1.80(2H,m),1.85-1.95(2H,m),2.85-3.05(2H,m),3.40-3.50(2H,m),3.70-3.90(5H,m),4.40(1H,m),4.90(1H,d),5.15(2H,s),6.71(1H,s),6.75(2H,d),6.95(2H,d),7.01(1H,d),7.30-7.55(8H,m),7.76-7.81(2H,m),7.89(1H,d)
工程３
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］−４−ヨードベンズアミジン 二トリフルオロ酢酸塩の合成
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（１−ベンジルオキシカルボニル−４−ピペリジルオキシ）フェニル］プロポキシ］−４−ヨードベンゾニトリル９７ｍｇ（０．１３ｍｍｏｌ）を４規定塩化水素のジオキサン溶液３ｍｌに溶解し、エタノール０．５ｍｌを加え、室温で４日間撹拌した。溶媒を減圧留去して得られた残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液３０ｍｌに溶解して室温で一晩撹拌した。溶媒を留去し、得られた残留物を氷冷下、２０％臭化水素を含む酢酸に溶解し２時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ３５ｍｇ（０．０４ｍｍｏｌ） 収率 ３１％
MS(ESI,m/z)635(MH+)
H-NMR(DMSO-d6)δ1.70-1.85(2H,m),2.00-2.12(2H,m),2.50-3.60(7H,m),4.05(2H,m),4.50(1H,m),6.74(2H,d),6.98(2H,d),7.21(1H,d),7.26(1H,s),7.37-7.67(5H,m),8.30(1H,d),8.16(1H,d),8.56(2H,brs),9.18(2H,brs),9.32(2H,brs)
実施例１８０
３−［４−アミジノ−２−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］フェニル］−２−オキソプロピオン酸 二トリフルオロ酢酸塩の合成
工程１
２−アセチルアミノ−３−［２−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］−４−シアノフェニル］アクリル酸メチルの合成
３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（１−ベンジルオキシカルボニル−４−ピペリジルオキシ）フェニル］プロポキシ］−４−ヨードベンゾニトリル１９７ｍｇ（０．２６ｍｍｏｌ）、２−アセトアミノアクリル酸メチル７４．４ｍｇ（０．５２ｍｍｏｌ）をアセトニトリル６ｍｌに溶解し、酢酸パラジウム（ＩＩ）７．３ｍｇ（０．０３ｍｍｏｌ）、トリ−ｏ−トリルホスフィン５５ｍｇ（０．１８ｍｍｏｌ）、トリブチルアミン９６ｍｇ（０．５２ｍｍｏｌ）を加え一晩加熱環流した。溶媒を留去し、酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。収量 １１１ｍｇ（０．１５ｍｍｏｌ） 収率 ５８％
H-NMR(CDCl3)δ1.68-1.80(2H,m),1.84-1.96(2H,m),2.07(3H,s),2.75-2.90(2H,m),3.40-3.50(2H,m),3.70-3.95(8H,m),4.40(1H,m),5.15(2H,s),5.35(1H,d),6.73(2H,d),6.89(1H,s),6.91(2H,d),7.22(1H,d),7.28-7.47(9H,m),7.53(1H,m),7.74-7.76(2H,m)
工程２
３−［４−アミジノ−２−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］フェニル］−２−オキソプロピオン酸 二トリフルオロ酢酸塩の合成
２−アセチルアミノ−３−［２−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］−４−シアノフェニル］アクリル酸メチル５００ｍｇを４規定塩化水素のジオキサン溶液１０ｍｌに溶解し、エタノール２ｍｌを加え室温で２日間撹拌した。溶媒を留去し得られた残渣をアンモニアを１０％含有する（ｗ／ｖ）エタノール溶液に溶解し、室温で３日間撹拌した。溶媒を留去し、得られた残留物を氷冷下、２０％臭化水素を含む酢酸１０ｍｌに溶解し３時間撹拌した。溶媒を留去して得られた残留物に３規定塩化水素２５ｍｌ、酢酸８ｍｌを加えて５時間加熱環流した。溶媒を減圧留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １５２ｍｇ（０．１９ｍｍｏｌ） 収率 ３０％
MS(ESI,m/z)595(MH+)
H-NMR(DMSO-d6)δ1.70-1.82(2H,m),2.00-2.12(2H,m),2.55(1H,m),2.90(1H,m),3.02-4.05(7H,m),4.15(1H,d,keto form),4.30(1H,d,keto form),4.50(1H,m),6.70-7.02(4H,m),6.91(1H,s,enol form),7.15-7.70(7H,m),8.23(1H,d),8.34(1H,d),8.6(2H,brs),9.05-9.30(4H,m)
実施例１８１
３−［４−アミジノ−２−［（２Ｓ）−３−［４−（１−アセトイミドイル−４−ピペリジルオキシ）フェニル］−２−（ベンゼンスルフォニルアミノ）プロポキシ］フェニル］−２−オキソプロピオン酸 二トリフルオロ酢酸塩の合成
３−［４−アミジノ−２−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］フェニル］−２−オキソプロピオン酸 二トリフルオロ酢酸塩１６２ｍｇ（０．２ｍｍｏｌ）をエタノール５ｍｌに溶解し、トリエチルアミン１．５ｇ（１５ｍｍｏｌ）、エチル アセトイミダート 塩酸塩４３５ｍｇ（３．５ｍｍｏｌ）を加え室温で１４日間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 １１７ｍｇ（０．１３５ｍｍｏｌ） 収率 ６７％
MS(ESI,m/z)636(MH+)
H-NMR(DMSO-d6)δ1.60-1.80(2H,m),1.95-2.10(2H,m),2.25(3H,s),2.60(1H,m),2.90(1H,m),3.30-4.10(7H,m),4.22(1H,d,keto form),4.45(1H,d,keto form),4.59(1H,m),6.70-7.00(4H,m),6.90(1H,s,enol form),7.15-7.67(7H,m),8.23(1H,d),8.33(1H,d),8.58(1H,brs),9.00-9.30(5H,m),9.80(1H,br,enol form)
実施例１８２
活性化血液凝固第Ｘ因子阻害活性の測定を、実施例９３と同様にして行った。代表的な化合物（実施例の番号）とその結果を下記表−２に示す。
実施例１８３
トロンビン阻害活性の測定を、実施例９４と同様にして行った。代表的な化合物（実施例の番号）とその結果を下記表−２に示す。
実施例１８４
抗血液凝固活性の測定
抗血液凝固活性はプロトロンビン時間（ＰＴ）測定法を用いて決定した。ＰＴ測定は以下に示す通りに行った。すなわち、健常人より採血を行い、３．８％クエン酸三ナトリウム水溶液を１０分の１容量加え、遠心操作により血漿を分離した。血漿４５μｌに評価化合物を含むＤＭＳＯ溶液５μｌを加え、室温で２分間インキュベートした。その血漿溶液を含む試験管をSysmex CA-3000全自動血液凝固測定装置（東亜用電子社製）に設置後、３７℃で３分間インキュベートし、Sysmex PT II（東亜医用電子社製、ウサギ脳組織トロンボプラスチン、１３．２ｍＭ塩化カルシウム）１００μｌを加えた。ＰＴは同装置により自動測定した。評価化合物の溶液の代わりにＤＭＳＯ５μｌを加えたものをコントロールとし、コントロールのＰＴを２倍に延長する評価化合物濃度の負の対数値を求め（ＰＴ２と略す）、抗血液凝固活性の指標とした。代表的な化合物の抗血液凝固活性を下記表−２に示す。
Figure 0004103147
但し、表中、実施例１２２の化合物はＮ−［３−（３−アミジノフェノキシ）プロピル］−４−アミジノベンズアミド 二トリフルオロ酢酸塩を、実施例１５４の化合物は３−［（２Ｓ）−２−（ベンゼンスルフォニルアミノ）−３−［４−（４−ピペリジルオキシ）フェニル］プロポキシ］ベンズアミジン 二トリフルオロ酢酸塩を、実施例１６７の化合物は４−［（２Ｓ）−１−［４−（４−ピペリジルオキシ）フェニル］−３−（３−アミジノフェノキシ）−２−プロピルスルファモイル］安息香酸 二トリフルオロ酢酸塩をそれぞれ示す。
この結果より、本発明のベンズアミジン誘導体は、活性化血液凝固第Ｘ因子に特異的な高い阻害活性を有しており、これに基づく高い抗血液凝固作用を示すことが分かる。
以下、実施例９５〜１８１で述べた本発明の化合物の構造式を示す。
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
実施例１８５
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−３−エトキシカルボニルプロポキシ］フェニル］アクリル酸メチル 二トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−ヒドロキシブタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−アスパラギン酸−β−ベンジルエステル１５．０ｇ（４６．４ｍｍｏｌ）、トリエチルアミン６．４７ｍｌ（４６．４ｍｍｏｌ）をテトラヒドロフラン２３０ｍｌに溶解し、氷冷下クロロギ酸エチル４．４ｍｌ（４６．４ｍｍｏｌ）を加え１５分間撹拌した。生じた析出物を吸引濾過により除去し、濾液に氷５ｇ、水素化ホウ素ナトリウム１．８ｇ（４６．４ｍｍｏｌ）を氷冷下加え１．５時間撹拌した。続いてここに１規定塩化水素水溶液を２００ｍｌを加え室温で更に１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１、ｖ／ｖ）で精製し表題化合物を得た。
収量 １０．２ｇ（３２．８ｍｍｏｌ） 収率 ７１％
1H-NMR(CDCl3)δ:1.42(9H,s),2.66(2H,d),3.65(2H,dd),4.00(1H,ddt),5.14(2H,s),7.35-7.40(5H,m)
工程２
３−ヒドロキシ−４−ヨードベンゾニトリルの合成
３−ヒドロキシ−４−ヨード安息香酸２２．３ｇ（８９．７ｍｍｏｌ）をテトラヒドロフラン３００ｍｌに溶解したものにクロロギ酸エチル１９．７ｍｌ（２０６ｍｍｏｌ）、トリエチルアミン２８．７ｍｌ（２０６ｍｍｏｌ）を０℃で加えた。１５分撹拌後、生成したトリエチルアミン塩酸塩を濾別し、アンモニアをバブリングして得られたテトラヒドロフラン溶液３００ｍｌに、濾液を０℃で加えた。室温で１０時間撹拌後、溶媒を減圧留去して得られた残留物をジオキサン４５０ｍｌに溶解し無水トリフルオロメタンスルホン酸１７．４ｍｌ（１１７ｍｍｏｌ）、ピリジン２１．８ｍｌ（２６９ｍｍｏｌ）を０℃で加えた。室温で１８時間撹拌後、溶媒を減圧留去して得られた残留物をクロロホルムを抽出溶媒とし常法に従って処理し油状残渣を得た。得られた残留物をテトラヒドロフラン：メタノール（１：１）１８０ｍｌに溶解したものに１規定水酸化ナトリウム水溶液９０ｍｌ（９０．０ｍｍｏｌ）を室温で加えた。そのまま４時間撹拌後、溶媒を減圧留去し、得られた残留物をジクロロメタンで洗浄した。続いて、１規定塩化水素で酸性とし酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトクラフィーで精製し表題化合物を得た。
収量 ９．２９ｇ（３７．９ｍｍｏｌ） 収率 ４２％
MS(FAB,m/z)246(MH+)
1H-NMR(CDCl3)δ:5.63(1H,br),6.96(1H,dd),7.23(1H,d),7.79(1H,d)
工程３
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（５−シアノ−２−ヨードフェノキシ）ブタン酸ベンジルの合成
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−ヒドロキシブタン酸ベンジル１０．１６ｇ（３２．８ｍｍｏｌ）をトルエン１００ｍｌに溶解し、３−ヒドロキシ−４−ヨードベンゾニトリル１０．５ｇ（４２．７ｍｍｏｌ）、トリフェニルホスフィン１１．２ｇ（４２．７ｍｍｏｌ）、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメチルアゾジカルボキシアミド７．４ｇ（４２．７ｍｍｏｌ）を氷冷下加え、室温で一晩撹拌した。溶媒を留去して得られた残留物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１、ｖ／ｖ）で精製し表題化合物を得た。
収量 １１．９ｇ（２２．１ｍｍｏｌ） 収率 ６７％
1H-NMR(CDCl3)δ:1.47(9H,s),2.90(2H,t),4.03(1H,dd),4.15(1H,dd),4.40-4.50(1H,m),5.19(2H,s),7.01(1H,d),7.30(1H,s),7.35-7.40(5H,m),7.92(1H,d)
工程４
（１Ｒ）−１−ベンジロキシカルボニルメチル−２−（５−シアノ−２−ヨードフェノキシ）エチルアンモニウム クロリドの合成
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（５−シアノ−２−ヨードフェノキシ）ブタン酸ベンジル１１．９ｇ（２２．１ｍｍｏｌ）を４規定塩化水素のジオキサン溶液１２０ｍｌに溶解し、０℃で１時間，続いて室温で２時間撹拌した。溶媒を留去し得られた油状残渣にヘキサンと酢酸エチルの混合溶媒（１：１、ｖ／ｖ）５０ｍｌを加え、析出物を濾取し表題化合物を得た。
収量 ６．１ｇ（１２．９ｍｍｏｌ） 収率 ５８％
MS(ESI,M/Z)437(MH+)
1H-NMR(DMSO-d6)δ:3.02(2H,d),3.94(1H,ddt),4.30(1H,dd),4.34(1H,dd),5.16(2H,s),7.26(1H,dd),7.32-7.40(5H,m),7.54(1H,s),8.03(1H,d),8.52(2H,br s)
工程５
（３Ｒ）−４−（５−シアノ−２−ヨードフェノキシ）−３−（４−シアノベンゾイルアミノ）ブタン酸ベンジルの合成
（１Ｒ）−１−ベンジロキシカルボニルメチル−２−（５−シアノ−２−ヨードフェノキシ）エチルアンモニウム クロリド４．７３ｇ（１０ｍｍｏｌ）、４−シアノ安息香酸２．９ｇ（２０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール３．０ｇ（２２ｍｍｏｌ）、トリエチルアミン６．１ｍｌ（４４ｍｍｏｌ）をジクロロメタン５０ｍｌに溶解し、氷冷下、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩４．２ｇ（２２ｍｍｏｌ）を加え、１０分間撹拌し、続いて室温で１時間撹拌した。水を加えて反応を停止し、ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１、ｖ／ｖ）で精製し表題化合物を得た。
収量 ２．８ｇ（５．０ｍｍｏｌ） 収率 ５０％
1H-NMR(CDCl3)δ:2.93(1H,dd),3.08(1H,dd),4.13(1H,dd),4.30(1H,dd),4.94(1H,dddd),5.14(1H,d),5.19(1H,d),6.96(1H,d),7.03(1H,dd),7.28-7.33(5H,m),7.72(2H,d),7.86(2H,d),7.88(1H,d)
工程６
２−アセトアミド−３−［２−［（２Ｒ）−３−エトキシカルボニル−２−（４−シアノベンゾイルアミノ）プロポキシ］−４−シアノフェニル］アクリル酸メチルの合成
（３Ｒ）−４−（５−シアノ−２−ヨードフェノキシ）−３−（４−シアノベンゾイルアミノ）ブタン酸ベンジル１．２８ｇ（２．２７ｍｍｏｌ）、２−アセトアミドアクリル酸メチル９７５ｍｇ（６．８１ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン４１５ｍｇ（１．３６ｍｍｏｌ）、トリエチルアミン０．９５ｍｌ（６．８１ｍｍｏｌ）、ジメチルホルムアミド０．５ｍｌをアセトニトリル８．０ｍｌに溶解し、酢酸パラジウム５６ｍｇ（０．２３ｍｍｏｌ）を室温で加え、９０℃で１２時間撹拌した。溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１、ｖ／ｖ）で精製し表題化合物を得た。
収量 ９９１ｍｇ（１．７１ｍｍｏｌ） 収率 ７５％
工程７
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−３−エトキシカルボニルプロポキシ］フェニル］アクリル酸メチル 二トリフルオロ酢酸塩の合成
２−アセトアミド−３−［２−［（２Ｒ）−３−エトキシカルボニル−２−（４−シアノベンゾイルアミノ）プロポキシ］−４−シアノフェニル］アクリル酸メチル３９８ｍｇ（０．６９ｍｍｏｌ）をエタノール１．０ｍｌに溶解し、４規定塩化水素のジオキサン溶液１０．０ｍｌを加え室温で２１時間撹拌した。溶媒を留去し得られた残留物をエタノール１０．０ｍｌに溶解し、炭酸アンモニウム１．０ｇ（１０．４ｍｍｏｌ）を加え、室温で１２時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １１８．６ｍｇ（０．１５ｍｍｏｌ）収率 ２２％
MS(ESI,M/Z)553(MH+)
1H-NMR(DMSO-d6)δ:1.17(3H,t),1.96(3H,s),2.81(1H,d),3.66(3H,s),4.08(2H,q),4.23(1H,dd),4.31(1H,dd),4.76(1H,br s),7.28(1H,s),7.44(1H,dd),7.53(1H,d),7.73(1H,d),7.90(2H,d),8.01(2H,d),8.87(1H,d),9.28(2H,s),9.32(2H,s),9.35(2H,s),9.42(2H,s),9.68(2H,s)
実施例１８６
（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］ブタン酸 二トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−２−（４−アミジノベンゾイルアミノ）−３−エトキシカルボニルプロポキシ］フェニル］アクリル酸メチル 二トリフルオロ酢酸塩１１８．６ｍｇ（０．１５ｍｍｏｌ）を６規定塩酸１０．０ｍｌに溶解し、６０℃で４時間撹拌する。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ５６．８ｍｇ（０．０８１ｍｍｏｌ）収率 ５４％
MS(ESI,M/Z)470(MH+)
1H-NMR(DMSO-d6)δ:2.27(2H,t),4.02(1H,dd),4.19(1H,dd),4.72(1H,br s).6.78(1H,s),7.35(1H,s),7.43(1H,d),7.90(2H,d),8.02(2H,d),9.10(1H,d),9.31(4H,s),9.42(4H,s)
実施例１８７
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−（４−ジメチルカルバモイルベンゾイルアミノ）プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−４−（５−シアノ−２−ヨードフェノキシ）−３−（４−ジメチルカルバモイルベンゾイルアミノ）ブタン酸ベンジルの合成
（１Ｒ）−１−ベンジロキシカルボニルメチル−２−（５−シアノ−２−ヨードフェノキシ）エチルアンモニウム クロリド２．０５ｇ（４．３３ｍｍｏｌ）、４−ジメチルカルバモイル安息香酸１．２５ｇ（６．４９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール９９４ｍｇ（７．３５ｍｍｏｌ）、トリエチルアミン２．７１ｍｌ（１９．４６ｍｍｏｌ）をジクロロメタン２５ｍｌに溶解し、氷冷下、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１．４１ｇ（７．３５ｍｍｏｌ）を加え、１０分間撹拌し、続いて室温で１８時間撹拌した。水を加えて反応を停止し、ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１、ｖ／ｖ）で精製し表題化合物を得た。
収量 ２．３０ｇ（３．７６ｍｍｏｌ）収率 ８７％
1H-NMR(DMSO-d6)δ:2.96(3H,s),2.97(1H,dd),3.07(1H,dd),3.12(3H,s),4.16(1H,dd),4.30(1H,dd),4.89-4.99(1H,m),5.14(1H,d),5.20(1H,d),6.97(1H,d),7.02(1H,dd),7.29-7.33(5H,m),7.44(2H,d),7.80(2H,d),7.88(1H,d)
工程２
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−（４−ジメチルカルバモイルベンゾイルアミノ）プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
（３Ｒ）−４−（５−シアノ−２−ヨードフェノキシ）−３−（４−ジメチルカルバモイルベンゾイルアミノ）ブタン酸ベンジル１．７６ｇ（２．８８ｍｍｏｌ）、２−アセトアミドアクリル酸メチル１．２４ｇ（８．６３ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン５３６ｍｇ（１．７３ｍｍｏｌ）、トリエチルアミン１．２ｍｌ（８．６３ｍｍｏｌ）、ジメチルホルムアミド０．５ｍｌをアセトニトリル１０ｍｌに溶解し、酢酸パラジウム７０ｍｇ（０．２９ｍｍｏｌ）を室温で加え、１００℃で５．５時間撹拌した。溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１、ｖ／ｖ）で精製した後、エタノール１．５ｍｌに溶解し、４規定塩化水素のジオキサン溶液１５ｍｌを加え室温で１５時間撹拌した。続いて、溶媒を留去し得られた残留物をエタノール２０．０ｍｌに溶解し、炭酸アンモニウム９７４ｍｇ（１０．１３ｍｍｏｌ）を加え、室温で１４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ５３６ｍｇ（０．７７ｍｍｏｌ）収率 ２７％
MS(ESI,M/Z)582(MH+)
1H-NMR(DMSO-d6)δ:1.08(3H,t),1.96(3H,s),2.81(2H,d),2.90(3H,s),2.99(3H,s),3.64(3H,s),4.07(2H,q),4.24(2H,t),4.70-4.79(1H,m),7.30(1H,s),7.42(1H,d),7.48(2H,d),7.70(1H,d),7.84(2H,d),8.69(1H,d),9.10(2H,s),9.32(2H,s),9.67(1H,s)
実施例１８８
（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−（４−ジメチルカルバモイルベンゾイルアミノ）ブタン酸 トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−（４−ジメチルカルバモイルベンゾイルアミノ）プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩１５１ｍｇ（０．２２ｍｍｏｌ）を６規定塩酸６ｍｌに溶解し、６０℃で３時間撹拌する。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ４９．２ｍｇ（０．０８ｍｍｏｌ）収率 ３７％
MS(ESI,M/Z)499(MH+)
1H-NMR(DMSO-d6)δ:2.69(1H,d),2.74(1H,d),2.87(3H,s),2.98(2H,s),4.22(1H,d),4.26(1H,d),4.60-4.76(1H,m),7.30(1H,s),7.40(1H,d),7.48(2H,d),7.50(1H,s),7.88(2H,d),8.32(1H,d),9.02(2H,s),9.26(2H,s)
実施例１８９
（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−（４−カルボキシルベンゾイルアミノ）ブタン酸 トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−（４−ジメチルカルバモイルベンゾイルアミノ）プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩５４ｍｇ（０．０８６ｍｍｏｌ）を６規定塩酸４ｍｌに溶解し、８０℃で２時間撹拌する。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １０．５ｍｇ（０．０２ｍｍｏｌ）収率 ２１％
MS(ESI,M/Z)472(MH+)
1H-NMR(DMSO-d6)δ:2.75(2H,d),4.24(2H,d),4.60-4.76(1H,m),6.79(1H,s),7.36(1H,d),7.45(1H,d),7.48(1H,s),7.90(2H,d),8.02(2H,d),8.32(1H,d),9.04(2H,s),9.25(2H,s)
実施例１９０
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
工程１
（３Ｒ）−４−（５−シアノ−２−ヨードフェノキシ）−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブタン酸ベンジルの合成
（１Ｒ）−１−ベンジロキシカルボニルメチル−２−（５−シアノ−２−ヨードフェノキシ）エチルアンモニウム クロリド２．０ｇ（４．２３ｍｍｏｌ）、４−ピロリジン−１−カルボニル）安息香酸１．０２ｇ（４．６５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール６３０ｍｇ（４．６５ｍｍｏｌ）、トリエチルアミン１．３０ｍｌ（９．３１ｍｍｏｌ）をジクロロメタン４０ｍｌに溶解し、氷冷下、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩８９０ｍｇ（４．６５ｍｍｏｌ）を加え、１０分間撹拌し、続いて室温で１８時間撹拌した。水を加えて反応を停止し、ジクロロメタンを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ２．６１ｇ（４．０９ｍｍｏｌ）収率 ９７％
1H-NMR(CDCl3)δ:1.83-2.02(4H,m),2.95(1H,dd),3.08(1H,dd),3.37(2H,t),3.64(2H,t),4.15(1H,dd),4.31(1H,dd),4.89-5.00(1H,m),5.13(1H,d),5.20(1H,d),6.97(1H,d),7.02(1H,dd),7.29-7.33(5H,m),7.54(2H,d),7.79(2H,d),7.88(1H,d)
工程２
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
（３Ｒ）−４−（５−シアノ−２−ヨードフェノキシ）−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブタン酸ベンジル２．６１ｇ（４．０９ｍｍｏｌ）、２−アセトアミドアクリル酸メチル１．８２ｇ（１２．６９ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン７７３ｍｇ（２．５４ｍｍｏｌ）、トリエチルアミン１．７７ｍｌ（１２．６９ｍｍｏｌ）、ジメチルホルムアミド０．５ｍｌをアセトニトリル１４ｍｌに溶解し、酢酸パラジウム１０３ｍｇ（０．４２ｍｍｏｌ）を室温で加え、１００℃で４時間撹拌した。溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１、ｖ／ｖ）で精製した後、エタノール４ｍｌに溶解し、４規定塩化水素のジオキサン溶液２０ｍｌを加え室温で１８時間撹拌した。続いて、溶媒を留去し得られた残留物をエタノール２０ｍｌに溶解し、炭酸アンモニウム１．１８ｇ（１２．２６ｍｍｏｌ）を加え、室温で１４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ６８０ｍｇ（０．９４ｍｍｏｌ）収率 ２３％
1H-NMR(DMSO-d6)δ:1.16(3H,t),1.78-1.91(4H,m),1.95(3H,s),2.79(2H,d),3.34(2H,t),3.47(2H,t),3.64(3H,s),4.07(2H,q),4.25(2H,t),4.73(1H,ddt),7.31(1H,s),7.43(1H,dd),7.52(1H,d),7.58(2H,d),7.80(1H,d),7.84(2H,d),8.69(1H,d),9.09(2H,s),9.33(2H,s),9.65(1H,br s)
実施例１９１
（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブタン酸 トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−カルボキシル−２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−カルボキシル−２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸 トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩１０５ｍｇ（０．１５ｍｍｏ１）を６規定塩酸６ｍｌに溶解し、４０℃で２時間、更に６０℃で１時間撹拌する。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物をそれぞれ得た。
（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブタン酸 トリフルオロ酢酸塩
収量 １８．２ｍｇ（０．０３ｍｍｏｌ）収率 ２０％
MS(ESI,M/Z)525(MH+)
1H-NMR(DMSO-d6)δ:1.75-1.92(4H,m),2.70(1H,d),2.76(1H,d),3.35(2H,d),3.47(2H,t),4.24(2H,d),4.70(1H,ddt),6.81(1H,s),7.46(1H,d),7.49(1H,s),7.57(2H,d),7.88(2H,d),8.33(1H,d),9.15(2H,m),9.27(2H,s)
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−カルボキシル−２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
収量 ３２．８ｍｇ（０．０５ｍｍｏｌ）収率 ３３％
MS(ESI,M/Z)580(MH+)
1H-NMR(DMSO-d6)δ:1.76-1.91(4H,m),1.95(3H,s),2.73(1H,d),3.34(2H,t),3.48(2H,t),3.65(3H,s),4.26(2H,t),4.64-4.77(1H,m),7.32(1H,s),7.44(1H,d),7.55(1H,s),7.59(2H,d),7.73(1H,d),7.88(2H,d),8.67(1H,d),9.13(2H,s),9.33(2H,s),9.63(1H,s)
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−カルボキシル−２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸 トリフルオロ酢酸塩の合成
収量 １３．２ｍｇ（０．０２ｍｍｏｌ）収率 １３％
MS(ESI,M/Z)566(MH+)
1H-NMR(DMSO-d6)δ:1.77-1.91(4H,m),1.94(3H,s),2.76(2H,d),3.35(2H,t),3.47(2H,t),4.27(2H,d),4.63-4.76(1H,m),7.36(1H,s),7.41(1H,dd),7.53(1H,d),7.57(2H,d),7.69(1H,d),7.86(2H,d),8.70(1H,d),9.19(2H,s),9.33(2H,s),9.50(1H,s)
実施例１９２
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピペリジル−４−オキシ）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル 二トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピペリジル−４−オキシ）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸エチル 二トリフルオロ酢酸塩の合成
工程１
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸エチルの合成
４−ヒドロキシ安息香酸エチル１．７ｇ（１０．２ｍｍｏｌ）、１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン１．７６ｇ（９．３ｍｍｏｌ）、トリフェニルホスフィン２．４４ｇ（９．３ｍｍｏｌ）をテトラヒドロフラン４０ｍｌに溶解し、アゾジカルボン酸ジエチル１．６２ｇ（９．３ｍｍｏｌ）を室温で加え一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 １．５７ｇ（４．５ｍｍｏｌ） 収率 ４４％
1H-NMR(CDCl3)δ:1.38(3H,t),1.50(9H,s)1.70-1.80(2H,m),1.90-2.00(2H,m),3.30-3.41(2H,m),3.63-3.75(2H,m),4.35(2H,q),4.55(1H,m),6.90(2H,d),8.00(2H,d)
工程２
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸の合成
４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸エチル８４７ｍｇ（２．４３ｍｍｏｌ）をエタノール５０ｍｌに溶解し、１規定水酸化ナトリウム溶液を５ｍｌを加え３日間室温で撹拌した。反応液を濃縮し、酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ６９７ｍｇ（２．２ｍｍｏｌ） 収率 ９２％
1H-NMR(CDCl3)δ:1.50(9H,s),1.70-2.00(4H,m),3.30-3.40(2H,m),3.65-3.75(2H,m),4.60(1H,s),6.95(2H,d),8.05(2H,d)
工程３
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピペリジル−４−オキシ）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル 二トリフルオロ酢酸塩の合成
（ｌＲ）−１−ベンジロキシカルボニルメチル−２−（５−シアノ−２−ヨードフェノキシ）エチルアンモニウム クロリド１．３３ｇ（２．８１ｍｍｏｌ）、４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）安息香酸１．１０ｇ（３．１０ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール４１９ｍｇ（３．１０ｍｍｏｌ）、トリエチルアミン０．８６ｍｌ（６．１９ｍｍｏｌ）をジクロロメタン３０ｍｌに溶解し、氷冷下、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩５９３ｍｇ（３．１０ｍｍｏｌ）を加え、１０分間撹拌し、続いて室温で１６時間撹拌した。水を加えて反応を停止し、ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてこのものをアセトニトリル１５ｍｌに溶解し、２−アセトアミドアクリル酸メチル１．２１ｇ（８．４３ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン５１３ｍｇ（１．６９ｍｍｏｌ）、トリエチルアミン１．１７ｍｌ（８．４３ｍｍｏｌ）、ジメチルホルムアミド０．５ｍｌを加えた。次いで、酢酸パラジウム６９ｍｇ（０．２８ｍｍｏｌ）を室温で加え、１００℃で１時間撹拌し、更に酢酸パラジウム３０ｍｇ（０．１２ｍｍｏｌ）を加え１００℃で４時間撹拌した。溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１、ｖ／ｖ）で精製した後、エタノール５ｍｌに溶解し、４規定塩化水素のジオキサン溶液３０ｍｌを加え室温で２０時間撹拌した。続いて、溶媒を留去し得られた残留物をエタノール２０ｍｌに溶解し、炭酸アンモニウム４．０ｇ（４１．６３ｍｍｏｌ）を加え、室温で５８時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ５１４ｍｇ（０．６１ｍｍｏｌ）収率 ２２％
1H-NMR(DMSO-d6)δ:1.16(3H,t),1.72-1.89(2H,m),1.95(3H,s),2.04-2.17(2H,m),2.79(2H,d),3.03-3.18(2H,m),3.20-3.32(2H,m),3.66(3H,s),4.04(2H,q),4.23(2H,d),4.66-4.79(1H,m),7.06(2H,d),7.28(1H,s),7.44(1H,dd),7.53(1H,d),7.73(1H,d),7.81(2H,d),8.46(1H,d),9.18(2H,s),9.34(2H,s),9.67(1H,br s)同時に２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピペリジル−４−オキシ）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸エチル 二トリフルオロ酢酸塩も得られた。
収量 １０４ｍｇ（０．１２ｍｍｏｌ） 収率 ４％
1H-NMR(DMSO-d6)δ:1.16(3H,t),1.19(3H,t),1.72-1.89(2H,m),1.96(3H,s),2.04-2.17(2H,m),2.78(2H,d),3.03-3.18(2H,m),3.20-3.32(2H,m),3.66(3H,s),4.08(2H,q),4.11(2H,q),4.22(2H,d),4.66-4.79(1H,m),7.06(2H,d),7.29(1H,s),7.44(1H,dd),7.52(1H,d),7.75(1H,d),7.82(2H,d),8.46(1H,d),9.20(2H,s),9.33(2H,s),9.65(1H,br s)
実施例１９３
（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（１−（１−イミノエチル）ピペリジル−４−オキシ）ベンゾイルアミノ］ブタン酸 二トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピペリジル−４−オキシ）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル 二トリフルオロ酢酸塩５１０ｍｇ（０．６１ｍｍｏｌ）をエタノール１０ｍｌに溶解し、トリエチルアミン１．７０ｍｌ（１２．１８ｍｍｏｌ）、エチル アセトイミダート 塩酸塩７５２ｍｇ（６．０９ｍｍｏｌ）を加え室温で１９時間撹拌した。溶媒を留去して得られた残留物を６規定塩酸１４ｍｌに溶解し、７０℃で４時間撹拌する。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ３２５ｍｇ（０．４８ｍｍｏｌ）収率 ７８％
MS(ESI,M/Z)568(MH+)
1H-NMR(DMSO-d6)δ:1.70-1.87(2H,m),2.02-2.15(2H,m),2.29(3H,s),2.68(1H,d),2.74(1H,d),3.48-3.58(2H,m),4.11-4.28(2H,m),4.60-4.72(1H,m),4.81(1H,br s),6.80(1H,s),7.07(2H,d),7.45(1H,d),7.48(1H,s),7.82(2H,d),8.33(1H,d),8.62(1H,s),9.14(2H,s),9.17(1H,s),9.26(2H,s)
実施例１９４
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸エチル トリフルオロ酢酸塩の合成
工程１
４−（ピロリジン−１−スルホニル）安息香酸の合成
ピロリジン１．０ｍｌ（１２ｍｍｏｌ）をピペリジン３３ｍｌに溶解し、氷冷下、４−クロロスルホ安息香酸２．２１ｇ（１０ｍｍｏｌ）を加え、３０分間撹拌し、更に室温で３０分間撹拌した。溶媒を留去して得られた残留物を３規定塩酸水溶液３０ｍｌに懸濁し、ジクロロメタンを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ２．３３ｇ（９．１３ｍｍｏｌ）収率 ９１％
1H-NMR(DMSO-d6)δ:1.04-1.11(4H,m),2.55-2.64(4H,m),7.34(2H,d),7.55(2H,d)
工程２
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
（１Ｒ）−１−ベンジロキシカルボニルメチル−２−（５−シアノ−２−ヨードフェノキシ）エチルアンモニウム クロリド１．５０ｇ（３．１７ｍｍｏｌ）、４−（ピロリジン−１−スルホニル）安息香酸８９１ｍｇ（３．４９ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール４７２ｍｇ（３．４９ｍｍｏｌ）、トリエチルアミン０．９７ｍｌ（６．９８ｍｍｏｌ）をジクロロメタン３１ｍｌに溶解し、氷冷下、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩６６９ｍｇ（３．４９ｍｍｏｌ）を加え、１０分間撹拌し、続いて室温で１７時間撹拌した。水を加えて反応を停止し、ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてこのものをアセトニトリル１２ｍｌに溶解し、２−アセトアミドアクリル酸メチル１．３６ｇ（９．５１ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン５７９ｍｇ（１．９０ｍｍｏｌ）、トリエチルアミン１．３３ｍｌ（９．５１ｍｍｏｌ）、ジメチルホルムアミド０．５ｍｌを加えた。次いで、酢酸パラジウム７８ｍｇ（０．３２ｍｍｏｌ）を室温で加え、１００℃で１時間撹拌し、更に酢酸パラジウム３５ｍｇ（０．１４ｍｍｏｌ）を加え１００℃で３時間撹拌した。再び２−アセトアミドアクリル酸メチル７００ｍｇ（４．８９ｍｍｏｌ）、トリス（２−メチルフェニル）ホスフィン２５０ｍｇ（０．８２ｍｍｏｌ）、トリエチルアミン３ｍｌ（２１．５ｍｍｏｌ）、酢酸パラジウム３３ｍｇ（０．１３ｍｍｏｌ）を加え、１００℃で更に２．５時間撹拌した。溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝３０：１、ｖ／ｖ）で精製した後、エタノール３ｍｌに溶解し、４規定塩化水素のジオキサン溶液３０ｍｌを加え室温で２２時間撹拌した。続いて、溶媒を留去し得られた残留物をエタノール３０ｍｌに溶解し、炭酸アンモニウム２．０ｇ（２０．８２ｍｍｏｌ）を加え、室温で３９時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ４８６ｍｇ（０．６４ｍｍｏｌ）収率 ２０％
1H-NMR(DMSO-d6)δ:1.17(3H,t),1.61-1.68(4H,m),1.94(3H,s),2.81(2H,d),3.12-3.29(4H,m),4.08(2H,q),4.21(1H,dd),4.28(1H,dd),4.76(1H,br s),7.29(2H,s),7.44(1H,dd),7.53(1H,d),7.72(1H,d),7 90(2H,d),8.00(2H,d),8.86(1H,d),9.11(2H,s),9.33(2H,s),9.67(1H,br s)
同時に２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸エチル トリフルオロ酢酸塩も得られた。
収量 ２０７ｍｇ（０．２７ｍｍｏｌ）収率 ８％
1H-NMR(DMSO-d6)δ:1.15(3H,t),1.17(3H,t),1.61-1.68(4H,m),1.95(3H,s),2.82(2H,d),3.12-3.29(4H,m),4.08(4H,q),4.21(1H,dd),4.29(1H,dd),4.76(1H,br s),7.29(2H,s),7.43(1H,dd),7.51(1H,d),7.74(1H,d),7 90(2H,d),8.01(2H,d),8.87(1H,d),9.08(2H,s),9.33(2H,s),9.64(1H,br s)
実施例１９５
（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］ブタン酸 トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−アミジノ−２−［（２Ｒ）−３−エトキシカルボニル−２−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］プロポキシ］フェニル］アクリル酸メチル
トリフルオロ酢酸塩２６９ｍｇ（０．３５ｍｍｏｌ）を６規定塩酸１４ｍｌに溶解し、７０℃で４時間撹拌する。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％（ｖ／ｖ）含有する水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １４６ｍｇ（０．２２ｍｍｏｌ）収率 ６２％
MS(ESI,M/Z)561(MH+)
1H-NMR(DMSO-d6)δ:1.58-1.70(4H,m),2.71(1H,dd),2.75(1H,dd),3.12-3.20(4H,m),4.20-4.30(2H,m),4.64-4.75(1H,m),6.80(1H,s),7.46(1H,d),7.47(1H,s),7.90(2H,d),8.02(2H,d),8.33(1H,d),9.03(2H,s),9.27(2H,s)
実施例１９６：Ｎ−［４−［１−アセトイミドイル−４−ピペリジルオキシ］フェニル］−Ｎ−［２−（３−アミジノフェノキシ）エチル］スルファモイル酢酸 二トリフルオロ酢酸塩の合成
工程１ １−ｔ−ブトキシカルボニル−４−（４−ニトロフェノキシ）ピペリジンの合成
４−ヒドロキシピペリジンをジ−ｔ−ブチルジカルボネートを用いて常法によりｔ−ブトキシカルボニル化して得た１−ｔ−ブトキシカルボニル−４−ヒドロキシピペリジン３．０２ｇ（１５．０ｍｍｏｌ）、４−ニトロフェノール２．０９ｇ（１５．０ｍｍｏｌ）、トリフェニルホスフィン４．７２ｇ（１８．０ｍｍｏｌ）をテトラヒドロフラン５０ｍｌに溶解し、アゾジカルボン酸ジエチル（４０％トルエン溶液）７．８４ｇ（１８．０ｍｍｏｌ）を室温で加え一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２．７４ｇ（８．５ｍｍｏｌ） 収率 ５７％
H-NMR(CDCl3)δ1.50(9H,s),1.75-1.86(2H,m),1.92-2.03(2H,m),3.36-3.43(2H,m),3.67-3.75(2H,m),4.58-4.64(1H,m),6.98(2H,d),8.20(2H,d)
工程２ １−ｔ−ブトキシカルボニル−４−（４−アミノフェノキシ）ピペリジンの合成
１−ｔ−ブトキシカルボニル−４−（４−ニトロフェノキシ）ピペリジン２．７４ｇ（８．５ｍｍｏｌ）をエタノール２０ｍｌに溶解し、１０％パラジウム炭素２０ｍｇを加え、１気圧の水素雰囲気下、室温で３時間撹拌した。吸引濾過によりパラジウム炭素を除き、濾液を一旦濃縮した後、ジクロロメタンを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ２．５９ｇ（８．０２ｍｍｏｌ） 収率 ９４％
H-NMR(CDCl3)δ1.47(9H,s),1.63-1.75(2H,m),1.82-1.93(2H,m),3.22-3.32(2H,m),3.68-3.78(2H,m),4.71-4.80(1H,m),6.63(2H,d),6.76(2H,d)
工程３ ３−（２−ブロモエトキシ）ベンゾニトリルの合成
２−ブロモエタノール０．７１ｍｌ（１０．０ｍｍｏｌ）、３−シアノフェノール１．４３ｇ（１２．０ｍｍｏｌ）、トリフェニルホスフィン３．１５ｇ（１２．０ｍｍｏｌ）をテトラヒドロフラン１００ｍｌに溶解し、アゾジカルボン酸ジエチル（４０％トルエン溶液）５．２２ｇ（１２．０ｍｍｏｌ）を室温で加え一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 １．６３ｇ（７．２ｍｍｏｌ） 収率 ７２％
H-NMR(CDCl3)δ3.67(2H,t),4.32(2H,t),7.14-7.19(2H,m),7.28(1H,d),7.40(1H,dd)
工程４ ３−［２−［［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）フェニル］アミノ］エトキシ］ベンゾニトリルの合成
１−ｔ−ブトキシカルボニル−４−（４−アミノフェノキシ）ピペリジン６１６ｍｇ（１．９１ｍｍｏｌ）、３−（２−ブロモエトキシ）ベンゾニトリル４３２ｍｌ（１．９１ｍｍｏｌ）、ヨウ化カリウム６３４ｍｇ（３．８２ｍｍｏｌ）をジメチルホルムアミド２０ｍｌに溶解し、炭酸カリウム２．６４ｇ（１９．１ｍｍｏｌ）を加え室温で１４時間撹拌した。溶媒を減圧留去した後、酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ３３４ｍｇ（０．７６ｍｍｏｌ） 収率 ４０％
H-NMR(CDCl3)δ1.48(9H,s),1.63-1.78(2H,m),1.81-1.96(2H,m),3.22-3.32(2H,m),3.52(2H,t),3.66-3.76(2H,t),4.17(2H,t),4.23-4.31(1H,m),6.63(2H,d),6.82(2H,d),7.14(1H,dd),7.16(1H,d),7.26(1H,dt),7.38(1H,dd)
工程５ スルホ酢酸エチルの合成
スルホ酢酸２．２１ｇ（１５．８ｍｍｏｌ）をエタノール３０ｍｌに懸濁させ、８０℃で５時間加熱還流した。溶媒を留去し表題化合物を得た。
収量 ２．１５ｇ（１２．８ｍｍｏｌ） 収率 ８１％
H-NMR(CDCl3)δ1.33(3H,t),4.07(2H,s),4.27(2H,q)
工程６ クロロスルホニル酢酸エチルの合成
スルホ酢酸エチル１．４３ｇ（８．５０ｍｍｏｌ）をオキシ塩化リン４．６ｍｌ（５１．０２ｍｍｏｌ）に加え、１００℃で５時間加熱還流した。溶媒を留去し表題化合物を得た。
収量 １．５０ｇ（８．０４ｍｍｏｌ） 収率 ９５％
H-NMR(CDCl3)δ1.38(3H,t),4.38(2H,q),4.60(2H,s)
工程７ Ｎ−［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）フェニル］−Ｎ−［２−（３−シアノフェノキシ）エチル］スルファモイル酢酸エチルの合成
３−［２−［［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）フェニル］アミノ］エトキシ］ベンゾニトリル３３４ｍｇ（０．７６ｍｍｏｌ）、トリエチルアミン２．７９ｍｌ（２０ｍｍｏｌ）をジクロロメタン１０ｍｌとピリジン１０ｍｌの混合溶媒中に溶解し、氷冷下クロロスルホニル酢酸エチル１．５０ｇ（８．０４ｍｍｏｌ）を加え、室温で１５時間撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２９９ｍｇ（０．５１ｍｍｏｌ） 収率 ６７％
H-NMR(CDCl3)δ1.34(3H,t),1.47(9H,s),1.69-1.81(2H,m),1.87-1.99(2H,m),3.35(2H,ddd),3.69(2H,ddd),3.98(2H,s),4.06(2H,t),4.09(2H,t),4.30(2H,q),4.44-4.52(1H,m),6.92(2H,d),7.01(1H,t),7.06(1H,ddd),7.24(1H,dt),7.34(1H,d),7.39(2H,d)
工程８ Ｎ−［４−［１−アセトイミドイル−４−ピペリジルオキシ］フェニル］−Ｎ−［２−（３−アミジノフェノキシ）エチル］スルファモイル酢酸 二トリフルオロ酢酸塩の合成
Ｎ−［４−（１−ｔ−ブトキシカルボニル−４−ピペリジルオキシ）フェニル］−Ｎ−［２−（３−シアノフェノキシ）エチル］スルファモイル酢酸エチル２９９ｍｇ（０．５１ｍｍｏｌ）をエタノール３ｍｌに溶解し、４規定塩化水素のジオキサン溶液１０ｍｌを加え室温で２０時間撹拌した。続いて、溶媒を留去し得られた残留物をエタノール１５ｍｌに溶解し、炭酸アンモニウム１．５ｇ（１５．６ｍｍｏｌ）を加え、室温で５５時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的とするアミジノ体のフラクションを凍結乾燥した。得られた固形物をエタノール１５ｍｌに溶解し、トリエチルアミン０．８４ｍｌ（６．０ｍｍｏｌ）、エチル アセトイミダート 塩酸塩３７０ｍｇ（３．０ｍｍｏｌ）を順次加え、室温で１８時間撹拌した。続いて、溶媒を留去して得られた残留物を６規定塩酸１４ｍｌに溶解し、４０℃で５時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １４４ｍｇ（０．１９ｍｍｏｌ）収率 ３８％
MS(ESI,m/z)518(MH+)
H-NMR(DMSO-d6)δ1.70-1.85(2H,m),2.01-2.14(2H,m),2.29(3H,s),3.45-3.57(2H,m),3.69-3.83(2H,m),4.04(4H,dd),4.18(2H,s),4.72(1H,br s),7.05(2H,d),7.20(1H,dd),7.31(1H,t),7.35(2H,d),7.39(1H,dd),7.50(1H,t),8.62(1H,s),9.16(1H,s),9.22(2H,s),9.28(2H,s)
実施例１９７：（３Ｒ）−３−（３−アミジノフェニルカルバモイル）−３−（４−ジメチルカルバモイルベンゾイルアミノ）プロピオン酸ベンジル トリフルオロ酢酸塩の合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−アスパラギン酸−β−ベンジルエステル１．７ｇ（５．２ｍｍｏｌ）、３−アミノベンズアミジン 二塩酸塩１．２ｇ（５．７ｍｍｏｌ）をピリジン３５ｍｌに溶解し、氷冷下、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩１．２ｇ（６．２ｍｍｏｌ）を加え、室温で１７時間撹拌した。溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、続いて、４規定塩化水素のジオキサン溶液３０ｍｌに溶解し、０℃で１時間，続いて室温で３時間撹拌した。溶媒を留去し得られた油状残渣をピリジン３０ｍｌとジメチルホルムアミド３０ｍｌの混合溶媒に溶解し、４−ジメチルカルバモイル安息香酸（実施例56の工程１の化合物）９９５ｍｇ（５．２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１．２ｇ（６．２ｍｍｏｌ）を順次加え室温で１８時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ６４２ｍｇ（１．０３ｍｍｏｌ）収率 ２０％
H-NMR(DMSO-d6)δ2.89(3H,s),2.94-3.02(2H,m),3.00(3H,s),5.05(1H,dd),5.13(1H,d),5.17(1H,d),7.28-7.38(5H,m),7.44(1H,d),7.51(2H,d),7.57(1H,dd),7.88(1H,d),7.93(2H,d),8.11(1H,s),8.99(1H,d),9.05(2H,s),9.32(2H,s)
実施例１９８：（３Ｒ）−３−（３−アミジノフェニルカルバモイル）−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロピオン酸ベンジル トリフルオロ酢酸塩の合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−アスパラギン酸−β−ベンジルエステル１．７ｇ（５．２ｍｍｏｌ）、３−アミノベンズアミジン 二塩酸塩１．２ｇ（５．７ｍｍｏｌ）をピリジン３５ｍｌに溶解し、氷冷下、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩１．２ｇ（６．２ｍｍｏｌ）を加え、室温で１７時間撹拌した。溶媒を留去し得られた残留物をシリカゲルカラムクロマトグラフィーで精製し、続いて、４規定塩化水素のジオキサン溶液３０ｍｌに溶解し、０℃で１時間，続いて室温で３時間撹拌した。溶媒を留去し得られた油状残渣をピリジン３０ｍｌとジメチルホルムアミド３０ｍｌの混合溶媒に溶解し、４−（ピロリジン−１−カルボニル）安息香酸（実施例●●●−１）１．１３ｇ（５．２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド 塩酸塩１．２ｇ（６．２ｍｍｏｌ）を順次加え室温で１８時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １０９ｍｇ（０．１７ｍｍｏｌ）収率 ３％
H-NMR(DMSO-d6)δ1.79-1.97(4H,m),2.94-3.02(2H,m),3.34-3.39(2H,m),3.44-3.52(2H,m),5.07(1H,dd),5.18(2H,s),7.29-7.38(7H,m),7.44(1H,d),7.59(1H,dd),7.87(1H,d),8.00(2H,d),8.11(1H,s),9.03(2H,s),9.08(1H,d),9.32(2H,s)
実施例１９９：（３Ｒ）−３−（３−アミジノフェニルカルバモイル）−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］プロピオン酸 トリフルオロ酢酸塩の合成
（３Ｒ）−３−（３−アミジノフェニルカルバモイル）−３−（４−ジメチルカルバモイルベンゾイルアミノ）プロピオン酸ベンジル トリフルオロ酢酸塩１０１ｍｇ（０．１６ｍｍｏｌ）を濃塩酸４ｍｌに溶解し、４０℃で５時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ４１ｍｇ（０．０８ｍｍｏｌ）収率 ４７％
MS(ESI,m/z)426(MH+)
H-NMR(DMSO-d6)δ2.89(3H,s),2.98(1H,dd),3.00(3H,s),3.27(1H,dd),4.86(1H,ddd),7.54(2H,d),7.67(1H,dd),7.72(1H,dd),7.80(1H,dd),7.87(1H,dd),7.93(2H,d),9.16(2H,s),9.47(2H,s),9.49(1H,d)
実施例２００：（３Ｒ）−３−（４−カルボキシベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸 トリフルオロ酢酸塩の合成（実施例１１９の副生成物）
（３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブタン酸エチル 二トリフルオロ酢酸塩４６６ｍｇ（０．７３ｍｍｏｌ）を濃塩酸１０ｍｌに溶解し４０℃で６時間撹拌した。塩化水素を留去し得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １７ｍｇ（０．０３４ｍｍｏｌ） 収率 ５％
MS(ESI,m/z)386(MH+)
H-NMR(DMSO-d6)δ2.75(2H,d),4.12(1H,dd),4.24(1H,dd),4.62-4.77(1H,m),7.32-7.42(3H,m),7.54(1H,dd),7.93(2H,d),8.02(2H,d),9.17(2H,s),9.28(2H,s)
実施例２０１ ３−［４−アミジノ−２−［２−［４−［２−（ピリジン−４−イル）エチル］ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩の合成
工程１ ４−［２−（ピリジン−４−イル）エチル］安息香酸 塩酸塩 の合成
４−（ジエトキシホスホリルメチル）安息香酸メチル（実施例42，工程１の化合物）４．８０ｇ（１６．８ｍｍｏｌ）をテトラヒドロフラン１００ｍｌに溶解させ、氷冷下、水素化ナトリウム６２０ｍｇ（１５．５ｍｍｏｌ）を加え、３０分撹拌後室温に戻して３０分撹拌した。ピリジン−４−アルデヒド１．３８ｇ（１２．９ｍｍｏｌ）を加え２０時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し得られた粗製物をメタノール３０ｍｌに溶解させ１０％パラジウム−炭素３００ｍｇを加え水素存在下２０時間撹拌した。セライト濾過後、溶媒を留去して得られた残留物を濃塩酸３０ｍｌに溶解させ４０℃で一晩撹拌した。溶媒を留去することにより表題化合物の粗製物を得た。
収量 ２．７ｇ（０．００８ｍｍｏｌ）収率 ９２％
工程２ ２−アセトアミド−３−［４−シアノ−２−［２−［４−［２−（ピリジン−４−イル）エチル］ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−シアノ−２−（２−アミノエトキシ）フェニル］アクリル酸メチル 塩酸塩１．５ｇ（４．４１ｍｍｏｌ）をジメチルホルムアミド５０ｍｌに溶解し、トリエチルアミン１．８４ ｍｌ（１３．２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール６５５ｍｇ （４．８５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩９３０ｍｇ（４．８５ｍｍｏｌ）、４−［２−（ピリジン−４−イル）エチル］安息香酸 塩酸塩 １．１０ｇ（４．８５ｍｍｏｌ）を加え室温で一晩撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。得られた粗製物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ８００ｍｇ（１．５６ｍｍｏｌ） 収率 ３５％
H-NMR(DMSO-d6)δ1.96(3H,s),2.82-2.98(4H,m),3.76(3H,s),3.78(2H,dt),4.30(2H,t),7.02(2H,dd),7.10(2H,d),7.17(2H,d),7.32(1H,d),7.42(2H,br),7.63(2H,d),8.42(2H,d)
工程３ ３−［４−アミジノ−２−［２−［４−［２−（ピリジン−４−イル）エチル］ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−シアノ−２−［２−［４−［２−（ピリジン−４−イル）エチル］ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩８００ｍｇ（１．５６ｍｍｏｌ）をエタノール１ｍｌ、４規定塩化水素を含むジオキサン溶液５ｍｌに溶解し三晩撹拌した。溶媒を留去後、エタノール５ｍｌに溶解させ、炭酸アンモニウム４４３ｍｇを加え一晩撹拌した。溶媒を留去後、濃塩酸２０ｍｌに溶解させ、４０℃で３時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ７０ｍｇ（０．１０ｍｍｏｌ） 収率 １３％
MS(ESI,m/z)475(MH+)
H-NMR(DMSO-d6)δ2.90-3.29(4H,m),3.69(2H,dt),4.25(2H,s,keto form),4.27(2H,t),6.82(1H,s,enol form),7.33(2H,d),7.37-7.49(2H,m),7.66(2H,d),7.78(2H,d),8.33(1H,d),8.67(2H,d),8.71(1H,t),9.08(2H,br),9.27(2H,br)
実施例２０２：２−（２Ｒ）−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩
工程１ ２−（２Ｒ）ミｔ−ブトキシカルボニルアミノ−５−ヒドロキシ−ペンタン酸ベンジルの合成
Ｎ−ｔ−ブトキシカルボニル−Ｄ−グルタミン酸−α−ベンジルエステル５ｇ（１５ｍｍｏｌ）、トリエチルアミン２．１ｇ（１５ｍｍｏｌ）をテトラヒドロフラン７５ｍｌに溶解し、氷冷下クロロギ酸エチル１．４３ｍｌ（１５ｍｍｏｌ）を加え２０分間撹拌した。生じた析出物を吸引濾過により除去し、濾液に氷５ｇ、水酸化ホウ素ナトリウム０．５７ｇ（１５ｍｍｏｌ）を氷冷下加え、１．５時間撹拌した。ここに１規定塩酸を３０ｍｌ加え室温で更に１時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し溶媒を留去して得られた残留物をシリカゲルクロマトグラフィーで精製し表題化合物を得た。
収量 １．６７ｇ（５．２ｍｍｏｌ） 収率 ３５％
H-NMR(CDCl3)δ1.40(9H,s),1.60-2.10(4H,m),3.60(2H,t),4.40(1H,m),5.20(3H,m),7.40(5H,m).
工程２ ２−（２Ｒ）ミｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジルエステルの合成
２−（２Ｒ）−ｔ−ブトキシカルボニルアミノ−５−ヒドロキシ−ペンタン酸ベンジル６．７７ｇ（２１ｍｍｏｌ）をテトラヒドロフラン１０５ｍｌに溶解し、３−シアノフェノール２．７４ｇ（２３ｍｍｏｌ）、トリフェニルホスフィン６．６ｇ（２５ｍｍｏｌ）、アゾジカルボン酸ジエチル（４０％トルエン溶液）１０ｇ（２３ｍｍｏｌ）を加え室温で一時間撹拌した。溶媒を留去して得られた残留物を酢酸エチルを抽出溶媒として常法に従って処理し、溶媒を留去して得られた残留物をシリカゲルクロマトグラフィーで精製し表題化合物を得た。
収量 ４．７９ｇ（１１．３ｍｍｏｌ） 収率 ５４％
H-NMR(CDCl3)δ1.42(9H,s),1.70-2.10(4H,m),3.95(2H,t),4.40(1H,m),5.10(1H,br),5.20(2H,m),7.06-7.10(2H,m),7.23(1H,d),7.35(5H,m)
工程３ ２−（２Ｒ）−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチルエステル 二トリフルオロ酢酸塩の合成
２−（２Ｒ）−ｔ−ブトキシカルボニルアミノ−５−（３−シアノフェノキシ）ペンタン酸ベンジルエステル４．７９ｇ（１１．３ｍｍｏｌ）を４Ｎ 塩化水素を含むジオキサン溶液４８ｍｌに溶解し、室温中２時間撹拌した。溶媒を留去し得られた脱ｔブトキシカルボニル体をジクロロメタン５７ｍｌ中撹拌し、４−シアノ安息香酸１．６ｇ（１１．３ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水）１．６８ｇ（１２．４ｍｍｏｌ）、トリエチルアミン３．５ｍｌ（２４．８ｍｍｏｌ）を加えた。氷冷下１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２．４ｇ（１２．４ｍｍｏｌ）を加え一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理して縮合体の粗生成物を得た。この粗生成物にジオキサン５ｍｌ、塩化水素を３０％含有する（Ｗ／Ｖ）エタノール４ｍｌ、４Ｎ 塩化水素を含むジオキサン溶液４０ｍｌを加え一晩撹拌した。溶媒を留去したのち、アンモニアを１０％含有する（ｗ／ｖ）エタノール溶液５０ｍｌ中、室温で一晩撹拌した。溶媒を留去して得られた残留物２５％をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １８７ｍｇ（０．２９ｍｍｏｌ） 収率１８．２％
MS(ESI,m/z)426(MH+),424(MH-).
H-NMR(DMSO-d6)δ1.20(3H,t),1.80-2.10(4H,m),4.10-4.20(4H,m),4.50(1H,m),7.30(1H,d),7.40(2H,m),7.55(1H,t)7.95(2H,d),8.05(2H,d),9.10(1H,d),9.20(2H,br),9.30(2H,br),9.38(2H,br),9.45(2H,br).
実施例２０３： ２−（２Ｒ）−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩
工程１ ２−（２Ｒ）−（４−アミジノベンゾイルアミノ）−５−（３−アミジノフェノキシ）ペンタン酸エチル 二トリフルオロ酢酸塩の合成
２−（２Ｓ）−（４−アミジノ−ベンゾイルアミノ）−５−（３−アミジノフェノキシ）−ペンタン酸エチルエステル 二トリフルオロ酢酸塩１．９ｇ（４．４６ｍｍｏｌ）を濃塩酸中、４０℃で４時間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ３４７ｍｇ（０．５５ｍｍｏｌ） 収率 ２０％
MS(ESI,m/z)398(MH+),396(MH-).
H-NMR(DMSO-d6)δ1.80-2.10(4H,m),4.13(2H,t),4.50(1H,m),7.30(1H,d),7.40(1H,d),7.40(1H,s),7.52(1H,t),7.95(2H,d),8.10(2H,d),9.00(1H,d),9.20(2H,br),9.38(2H,br),9.40(2H,br),9.52(2H,br).
実施例２０４： ４−（３−アミジノフェノキシ）−３−［［１−（ピリジン−４−イル）−ピペリジン−４−カルボニル］アミノ］ブチル酸 二トリフルオロ酢酸塩の合成
工程１ １−（ピリジン−４−イル）−ピペリジン−４−カルボン酸クロライドの合成
１−（ピリジン−４−イル）−ピペリジン−４−カルボン酸 塩酸塩７ｇ（３４ｍｍｏｌ）をジクロロメタン３４０ｍｌ中撹拌し、ジメチルホルムアミド１ｍｌ、二塩化オキサリル１０．４ｍｌ（１０９ｍｍｏｌ）加え、室温で１時間撹拌した。溶媒を留去したのち、真空ポンプで１時間乾燥させ、表題化合物を得た。
収量 ７．９ｇ（３５ｍｍｏｌ）
工程２ ４−（３−シアノフェノキシ）−３−［［１−（ピリジン−４−イル）−ピペリジン−４−カルボニル］アミノ］ブチル酸ベンジルエステルの合成
１−（ピリジン−４−イル）ピペリジン−４−カルボン酸クロライド３．７ｇ（１６．５ｍｍｏｌ）、（３Ｒ）−３−アミノ−４−（３−シアノフェノキシ）ブチル酸ベンジルエステル 塩酸塩４ｇ（１２ｍｍｏｌ）をジクロロメタン６０ｍｌ中撹拌し、トリエチルアミン５．９５ｍｌ（４２．７ｍｍｏｌ）、ジメチルホルムアミド１ｍｌ、４−ジメチルアミノピリジン５０ｍｇを加え一晩撹拌した。反応液をジクロロメタンで抽出し、１規定水酸化ナトリウム、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去した。残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出した。目的物のフラクションの溶媒を留去し、１Ｎ 水酸化ナトリウムを加え、ジクロロメタンを抽出溶媒として常法に従って処理し、表題化合物を得た。
収量 １．５８ｇ（３．１７ｍｍｏｌ） 収率 １９％
工程３ ４−（３−アミジノフェノキシ）−３−［［１−（ピリジン−４−イル）−ピペリジン−４−カルボニル］アミノ］ブチル酸 二トリフルオロ酢酸塩の合成
４−（３−シアノフェノキシ）−３−［［１−（ピリジン−４−イル）−ピペリジン−４−カルボニル］アミノ］ブチル酸ベンジルエステル１．５８ｇ（３．１７ｍｍｏｌ）とエタノール１．６ｍｌを４Ｎ 塩化水素を含むジオキサン溶液１６ｍｌ中、一晩撹拌した。溶媒を留去し、エタノール溶液１０ｍｌと炭酸アンモニウム０．５ｇを加え一晩撹拌し、溶媒を留去した。得られた残留物を濃塩酸３ｍｌ中、４０℃で４時間撹拌した。溶媒を留去し、得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ５９４ｍｇ（０．９１ｍｍｏｌ） 収率 ２９％
MS(ESI,m/z)426(MH+)
H-NMR(DMSO-d6)δ1.50-1.61(2H,m),1.70-1.90(2H,m),2.50-2.85(3H,m),3.15-3.30(2H,m),4.00-4.20(2H,m),4.15-4.30(2H,m),4.40(1H,m),7.20(2H,d),7.30(1H,d),7.41(1H,s),7.42(1H,d),7.53(1H,t),8.17(1H,d),8.22(2H,d),9.29(2H,br),9.38(2H,br).
実施例２０５： ３−［４−アミジノ−２−［２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 トリフルオロ酢酸塩の合成
工程１ ２−アセトアミド−３−［４−シアノ−２−［２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチルの合成
２−アセトアミド−３−［４−シアノ−２−（２−アミノエトキシ）フェニル］アクリル酸メチル 塩酸塩２．５ｇ（７．４ｍｍｏｌ）をジメチルホルムアルデヒドに溶解し、４−（ピロリジン−１−カルボニル）安息香酸１．５６ｇ（８．１ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール１．１ｇ（８．１ｍｍｏｌ）、トリエチルアミン１．５３ｍｌ、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１．５５ｇ（８．１ｍｍｏｌ）を加え室温で一晩撹拌した。溶媒を留去して得られた残留物を、酢酸エチルを抽出溶媒として常法に従って処理し、溶媒を留去して得られた残留物をヘキサンで洗浄、乾燥し表題化合物を得た。
収量 １．８０ｇ（３．６８ｍｍｏｌ） 収率 ５０％
H-NMR(DMSO-d6)δ1.78-1.90(4H,m),1.95(3H,s),3.30-3.50(4H,m),3.60-3.65(3H,s),3.70(2H,dt),4.30(2H,t),7.20(1H,s),7.41(1H,d),7.55-7.70(4H,m),7.85(2H,d),8.75(1H,t),9.65(1H,s).
工程２ ３−［４−アミジノ−２−［２−［４−（ピロリジン−１−カルボニルベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−シアノ−２−［２−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸メチル１．８０ｇ（３．６８ｍｍｏｌ）とエタノール１ｍｌを４Ｎ塩化水素を含むジオキサン２０ｍｌ中、二晩撹拌した。溶媒を留去した後、エタノール２０ｍｌと炭酸アンモニウム１．０ｇを加え一晩撹拌した。溶媒を留去した後、６規定塩酸２０ｍｌを加え、８０℃で１．５時間加熱環流した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ３４５ｍｇ（０．５９ｍｍｏｌ） 収率 １６％
MS(ESI,m/z)467(MH+)
H-NMR(DMSO-d6)δ1.75-1.95(4H,m),3.30-3.50(4H,m),3.72(2H,dt),4 30(2H,t),4.25(2H,s,ケト体),6.81(1H,s,エノール体),7.35-7.50(2H,m),7.60(2H,d),7.89(2H,d),8.33(1H,d),8.85(1H,br),9.01(2H,br),9.27(2H,br),9.80(1H,br,エノール体)
実施例２０６： ３−［４−アミジノ−２−［２−［［１−（ピリジン−４−イル）ピペリジン−４−カルボニル］アミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩の合成
工程１ ２−アセトアミド−３−［４−シアノ−２−［２−［［１−（ピリジン−４−イル）ピペリジン−４−カルボニル］アミノ］エトキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−シアノ−２−（２−アミノエトキシ）フェニル］アクリル酸メチル 塩酸塩１．０ｇ（２．９４ｍｍｏｌ）、１−（ピリジン−４−イル）ピペリジン−４−カルボン酸 塩酸塩０．７９ｇ（３．２４ｍｍｏｌ）、トリエチルアミン１．６４ｍｌをジメチルホルムアミド中撹拌し、そこへ氷冷下ブロモトリピロリジノホスホニウム ヘキサフルオロホスファート１．５１ｇ（３．２４ｍｍｏｌ）加えた後、室温で一晩撹拌した。溶媒を減圧留去し、得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ３６０ｍｇ（０．７３ｍｍｏｌ） 収率 ２５％
H-NMR(DMSO-d6)δ1.50-1.70(2H,m),1.75-1.90(2H,m),1.95(3H,s),2.50(1H,m),3.15-3.30(2H,m),3.42(2H,dt),3.65(3H,s),4.10-4.22(4H,m),7.15-7.21(3H,m),7.44(1H,d),7.58(1H,s),7.68(1H,d),8.09(1H,t),8.21(2H,d),9.65(1H,s)
工程２ ３−［４−アミジノ−２−［２−［［１−（ピリジン−４−イル）ピペリジン−４−カルボニル］アミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩の合成
２−アセトアミド−３−［４−シアノ−２−［２−［［１−（ピリジン−４−イル）ピペリジン−４−カルボニル］アミノ］エトキシ］フェニル］アクリル酸メチル トリフルオロ酢酸塩 ３６０ｍｇ（０．７３ｍｍｏｌ）とエタノール０．５ｍｌを４Ｎ 塩化水素を含むジオキサン溶液１０ｍｌ中、二晩撹拌した。溶媒を留去し、エタノール５ｍｌと炭酸アンモニウム０．２１ｇを加え室温で一晩撹拌した。溶媒を留去して得られた残留物に６規定塩酸１０ｍｌを加え、８０℃で１．５時間加熱環流した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 ２０５ｍｇ（０．３０ｍｍｏｌ） 収率 ４１％
MS(ESI,m/z)454(MH+)
H-NMR(DMSO-d6)δ1.50-1.70(2H,m),1.80-1.95(2H,m),2.60(1H,m),3.18-3.30(2H,m),3.43-3.60(2H,m),4.10-4.30(4H,m),6.80(1H,s,エノール体),7.18(2H,d),7.35-7.48(2H,m),8.22(2H,d),8.34(1H,d)9.15(2H,br),9.30(2H,br),9.80(1H,br,エノール体).
実施例２０７：Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（４−メトキシベンゾイル）ベンズアミド トリフルオロ酢酸塩の合成
工程１ ４−（４−メトキシベンゾイル）安息香酸メチルの合成
塩化アルミニウム２．１ｇ（１６ｍｍｏｌ）、テレフタル酸モノメチルエステルクロライド２、４ｇ（１２ｍｍｏｌ）をジクロロメタン１５ｍｌ中、氷冷下撹拌し、そこへアニソール１．０ｇ（９．３ｍｍｏｌ）を加えた。二時間後、室温に昇温し一晩撹拌した。ジクロロメタンを抽出溶媒として常法に従って処理し、溶媒を留去した。得られた残留物をシリカゲルクロマトグラフィーで精製し表題化合物を得た。
収量 ６１０ｍｇ（２．３ｍｍｏｌ） 収率 ２５％
H-NMR(CDCl3)δ3.90(3H,s),3.98(3H,s),6.89(2H,d),7.79(2H,d),7.81(2H,d),8.14(2H,d)
工程２ ４−（４−メトキシベンゾイル）安息香酸の合成
４−（４−メトキシベンゾイル）安息香酸メチル６１０ｍｇ（２．３ｍｍｏｌ）をエタノール４０ｍｌ中撹拌し、１規定水酸化ナトリウム水溶液６ｍｌ加え、三日間撹拌した。反応液を留去した後、１Ｎ 塩酸を加え、酢酸エチルを抽出溶媒として常法に従って処理し表題化合物を得た。
収量 ３１３ｍｇ（１．２２ｍｍｏｌ） 収率 ５３％
H-NMR(DMSO-d6)δ3.88(3H,s),7.11(2H,d),7.78(2H,d),7.78(2H,d),8.09(2H,d).
工程３ Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−（４−メトキシベンゾイル）ベンズアミド トリフルオロ酢酸塩の合成
４−（４−メトキシベンゾイル）安息香酸１５０ｍｇ（０．５９ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル 塩酸塩１２８ｍｇ（０．６４ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール８７ｍｇ（０．６４ｍｍｏｌ）、トリエチルアミン０．１ｍｌ、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１２３ｍｇ（０．６４ｍｍｏｌ）をジクロロメタン中で一晩撹拌した。ジクロロメタンを抽出溶媒として常法に従って処理した。得られた縮合体の粗生成物を４Ｎ 塩化水素を含むジオキサン１０ｍｌ中、エタノール１ｍｌを加え二晩撹拌した。溶媒を留去し、炭酸アンモニウム０．２ｇ、エタノール１０ｍｌを加え、一晩撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより表題化合物を得た。
収量 １０３ｍｇ（０．１９ｍｍｏｌ） 収率 ３２％
MS(ESI,m/z)418(MH+)
H-NMR(DMSO-d6)δ3.70(2H,dt),3.85(3H,s),4.25(2H,t),7.10(2H,d),7.30-7.43(3H,m),7.54(1H,t),7.76(2H,d),7.76(2H,d),8.01(2H,d),8.95(1H,t),9.10(2H,br),9.30(2H,br).
実施例２０８：（２Ｓ）−２−（４−ジメチルカルバモイルベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸エチル トリフルオロ酢酸塩の合成
（２Ｓ）−２−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル（実施例91の工程１の化合物）、４−ジメチルカルバモイル安息香酸を原料として実施例91の工程２と同様にして得た（２Ｓ）−２−（４−ジメチルカルバモイルベンゾイルアミノ）−４−（３−シアノフェノキシ）ブチル酸ベンジルを実施例１の工程６と同様に処理して表題化合物を得た。
MS(ESI,m/z)441(MH+)
H-NMR(DMSO-d6)δ1.20(3H,t),2.25(2H,m),2.83(3H,s),3.00(3H,s),4.10-4.30(4H,m),4.70(1H,m),7.30(1H,d),7.35(1H,s),7.37(1H,d),7.50(2H,d),7.51(1H,t),7.92(2H,d),8.92(1H,d),9.05(2H,br),9.30(2H,br).
実施例２０９：（２Ｓ）−２−（４−アミジノベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸エチル 二トリフルオロ酢酸塩の合成
（２Ｓ）−２−（４−シアノベンゾイルアミノ）−４−（３−シアノフェノキシ）ブチル酸ベンジル（実施例91の工程２の化合物）を実施例１の工程６と同様に処理して表題化合物を得た。
MS(ESI,m/z)412(MH+)
H-NMR(DMSO-d6)δ1.20(3H,t),2.22-2.40(2H,m),4.10-4.30(4H,m),4.70(1H,m),7.31(1H,d),7.37(1H,s),7.39(1H,d),7.53(1H,t),7.92(2H,d),8.07(2H,d),9.12(1H,d),9.20(2H,br),9.28(2H,br),9.33(2H,br),9.43(2H,br).
実施例２１０：（２Ｓ）−２−（４−カルバモイルベンゾイルアミノ）−４−（３−アミジノフェノキシ）ブチル酸 トリフルオロ酢酸塩の合成
実施例91の工程３の副生成物として表題化合物を得た。
MS(ESI,m/z)385(MH+)
H-NMR(DMSO-d6)δ2.20-2.40(2H,m),4.20(2H,m),4.65(1H,m),7.26-7.40(3H,m),7.51(1H,br),7.52(1H,t),7.95(4H,s),8.10(1H,br),8.87(1H,d),9.06(2H,br),9.29(2H,br).
実施例２１１：４−（３−アミジノフェノキシ）−３−（３Ｒ）−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩の合成
工程１ ４−（１−ピロリジルカルボニル）安息香酸の合成
テレフタル酸モノメチルエステル クロリド２９．０ｇ（０．１４６ｍｏｌ）、ピロリジン１４．２ｇ（２００ｍｍｏｌ）、トリエチルアミン２１．０ｇ（２０８ｍｍｏｌ）をジクロロメタン３５０ｍｌ中で反応させ、常法により処理し４−（１−ピロリジルカルボニル）安息香酸 メチルエステルを得た。このエステル体２９．０ｇを水酸化ナトリウム１２．０ｇと水７０ｍｌ、メタノール７０ｍｌ、テトラヒドロフラン７０ｍｌの混合溶媒中で加水分解し、反応終了後溶媒を留去した。１Ｎ 塩酸を加えジクロロメタンを抽出溶媒として常法に従って処理し、表題化合物を得た。
収量 ２３．７ｇ（１０８ｍｍｏｌ）
1H-NMR(DMSO-d6)δ:1.75-1.90(4H,m),3.30-3.50(4H,m),7.62(2H,d),7.99(2H,d),13.14(1H,br)
工程２ ４−（３−シアノフェノキシ）−３−（３Ｒ）−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブチル酸 ベンジルエステルの合成
（３Ｒ）−３−アミノ−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステル塩酸塩（実施例５２の工程２の化合物）１．８ｇ（５．２ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水）７０３ｍｇ（５．２ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩９９７ｍｇ（５．２ｍｍｏｌ）、トリエチルアミン５２６ｍｇ（５．２ｍｍｏｌ）、４−（１−ピロリジルカルボニル）安息香酸１．１４ｇ（５．２ｍｍｏｌ）をジクロロメタン中一晩撹拌した。反応液を１Ｎ 塩酸、１Ｎ 水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を留去した。得られた残留物をシリカゲルクロマトグラフィー（酢酸エチル）で精製し、表題化合物を得た。
収量 １．８２ｇ（３．５６ｍｍｏｌ） 収率 ６９％
1H-NMR(CDCl3)δ:1.85-2.05(4H,m),2.80-3.00(2H,m),3.35(2H,t),3.65(2H,t),4.10-4.25(2H,m),4.85(1H,m),5.20(2H,s),7.10(1H,s),7.12(1H,d),7.24-7.40(7H,m),7.54(2H,d),7.76(2H,d)
工程３ ４−（３−アミジノフェノキシ）−３−（３Ｒ）−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩の合成
４−（３−シアノフェノキシ）−３−（３Ｒ）−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブチル酸 ベンジルエステル１．８２ｇ（３．５６ｍｍｏｌ）とエタノール３ｍｌを４Ｎ塩化水素を含有するジオキサン中、２日間撹拌した。溶媒を留去して得られた残留物にエタノール２０ｍｌ、炭酸アンモニウム（アンモニアとして純度３０％）１．０ｇを加えて一晩撹拌した。溶媒を留去して得られた残留物に濃塩酸２０ｍｌを加え４０℃で一晩撹拌した。溶媒を留去し、得られた残留物をオクタドデシル基化学結合型シリカゲルを充填材とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥し、表題化合物を得た。
収量 ９１３ｍｇ（１．６５ｍｍｏｌ） 収率 ４６％
MS(ESI,m/z)439(MH+)
1H-NMR(DMSO-d6)δ:1.70-1.90(4H,m),2.75(2H,d),3.35(2H,t),3.50(2H,t),4.05-4.30(2H,m),4.70(1H,m),7.32-7.43(3H,m),7.54(1H,t),7.60(2H,d),7.88(2H,d),8.64(1H,d),9.10(2H,br),9.28(2H,br)
実施例２１２：４−（３−アミジノフェノキシ）−３−（３Ｒ）−（４−ジメチルカルバモイル−ベンゾイルアミノ）ブチル酸 エチルエステル トリフロオロ酢酸塩の合成
４−（３−シアノフェノキシ）−（３Ｒ）−３−（４−ジメチルカルバモイル−ベンゾイルアミノ）ブチル酸 ベンジルエステル（実施例５６の工程２の化合物）１．８７ｇ（３．９８ｍｍｏｌ）、エタノール３ｍｌを４Ｎ塩化水素を含有するジオキサン中２日間撹拌した。溶媒を留去して得られた残留物にエタノール２０ｍｌ、炭酸アンモニウム（アンモニアとして純度３０％）１．１ｇを加えて一晩撹拌した。溶媒を留去して得られた残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 ８９５ｍｇ（１．６１ｍｍｏｌ） 収率 ４１％
MS(ESI,m/z)441(MH+)
1H-NMR(DMSO-d6)δ:1.15(3H,t),2.80(2H,d),2.90(3H,s),3.00(3H,s),4.10(2H,q),4.00-4.25(2H,m),4.70(1H,m),7.30-7.40(3H,m),7.50(2H,d),7.54(1H,t),7.87(2H,d),8.65(1H,d),9.04(2H,br),9.27(2H,br)
実施例２１３：３−［４−アミジノ−２−［２−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩
工程１ ［２−（５−シアノ−２−ヨードフェノキシ）エチル］カルバミン酸 ｔ−ブチルエステルの合成
３−ヒドロキシ−４−ヨードベンゾニトリル（実施例７９の工程２の化合物）、ｔ−ブチル（２−クロロエチル）カルバマート（なお、ｔ−ブチル（２−クロロエチル）カルバマートは２−クロロエチルアミン塩酸塩を用いて実施例１工程１と同様にして得た。）を出発原料とし、実施例１の工程２と同様にして表題化合物を得た。
1H-NMR(CDCl3)δ:1.45(9H,s),3.62(2H,dt),4.10(2H,t),5.05(1H,br),6.96-7.06(2H,m),7.90(1H,d)
工程２ ２−アセタミド−３−［２−（２−ｔ−ブトキシカルボニルアミノ−エトキシ）−４−シアノフェニル］アクリル酸 メチルエステルの合成
［２−（５−シアノ−２−ヨードフェノキシ）エチル］カルバミン酸 ｔ−ブチルエステル１５．３ｇ（３９．５ｍｍｏｌ）、２−アセタミドアクリル酸メチルエステル９．０５ｇ（６３．２ｍｍｏｌ）、トリエチルアミン１１ｍｌ（７９ｍｍｏｌ）、酢酸パラジウム（II）１．３ｇ、トリス（２−メチルフェニル）ホスフィン７．３０ｇ（２４．０ｍｍｏｌ）をアセトニトリル１５０ｍｌ中一晩撹拌した。溶媒を留去し、シリカゲルクロマトグラフィー（酢酸エチル−ヘキサン）で精製して得た粗生成物をヘキサン、ヘキサン−酢酸エチルの混合溶媒で洗浄した後、真空乾燥し表題化合物を得た。
収量 １０．２３ｇ（２５．４ｍｍｏｌ） 収率 ６４％
1H-NMR(DMSO-d6)δ:1.38(9H,s),1.95(3H,s),3.35(2H,dt),3.70(3H,s),4.10(2H,t),7.03(1H,t),7.20(1H,s),7.43(1H,d),7.55(1H,s),7.68(1H,d),9.65(1H,s)
工程３ ２−アセタミド−３−［２−（２−アミノエトキシ）−４−シアノフェニル］アクリル酸 メチルエステル 塩酸塩の合成
２−アセタミド−３−［２−（２−ｔ−ブトキシカルボニルアミノ−エトキシ）−４−シアノフェニル］アクリル酸 メチルエステル７．７５ｇ（１９．２ｍｍｏｌ）へジオキサン３０ｍｌを加えて撹拌し、そこへ４Ｎ 塩化水素を含有するジオキサン８０ｍｌを加え、室温で１時間撹拌した。溶媒を留去し、残留物を酢酸エチルに懸濁させて濾取することにより表題化合物を得た。
収量 ４．３８ｇ（１２．９ｍｍｏｌ） 収率 ６７％
1H-NMR(DMSO-d6)δ:1.95(3H,s),3.25(2H,dt),3.70(3H,s),4.30(2H,t),7.28(1H,s),7.48(1H,d),7.62(1H,s),7.70(1H,d),8.20(3H,br),9.75(1H,s)
工程４ ４−（Ｎ，Ｎ−ジメチルアミジノ）安息香酸 塩酸塩の合成
４−（Ｎ，Ｎ−ジメチルアミジノ）安息香酸 エチルエステル（実施例７の工程１の化合物）を６Ｎ 塩酸で６時間加熱環流した後、溶媒を留去し表題化合物を得た。1H-NMR(DMSO-d6)δ:2.95(3H,s),3.25(3H,s),7.75(2H,d),8.15(2H,d),9.25(1H,br),9.50(1H,br)
工程５ ２−アセタミド−３−［４−シアノ−２−［２−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸 メチルエステル トリフルオロ酢酸塩の合成
２−アセタミド−３−［２−（２−アミノエトキシ）−４−シアノフェニル］アクリル酸 メチルエステル 塩酸塩３．５４ｇ（１０．４ｍｍｏｌ）、４−（Ｎ，Ｎ−ジメチルアミジノ）安息香酸 塩酸塩２．６２ｇ（１１．５ｍｍｏｌ）、ジイソプロピルエチルアミン３．５ｍｌ（１９．６ｍｍｏｌ）、ブロモ−トリピロリジノホスホニウム ヘキサフルオロホスファート６．１９ｇ（１３．３ｍｍｏｌ）をジメチルホルムアミド中室温で一晩撹拌した。ジメチルホルムアミドを減圧留去し、酢酸エチルで抽出後、１Ｎ 水酸化ナトリウム、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を留去して得られた残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 １．０ｇ（１．７３ｍｍｏｌ） 収率 １７％
1H-NMR(DMSO-d6)δ:1.95(3H,s),2.98(3H,s),3.22(3H,s),3.65(3H,s),3.70(2H,dt),4.30(2H,t),7.21(1H,s),7.44(1H,d),7.62-7.74(4H,m),8.03(2H,d),8.88(1H,t),8.96(1H,s),9.35(1H,s),9.67(1H,s)
工程６ ３−［４−アミジノ−２−［２−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］エトキシ］フェニル］−２−オキソ−プロピオン酸 二トリフルオロ酢酸塩の合成
２−アセタミド−３−［４−シアノ−２−［２−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］エトキシ］フェニル］アクリル酸 メチルエステル トリフルオロ酢酸塩１．０ｇ（１．７３ｍｍｏｌ）、エタノール１．０ｍｌを４Ｎ 塩化水素を含むジオキサン２０ｍｌ中で室温、２日間撹拌した。溶媒を留去して得られた残留物にエタノール２０ｍｌ、炭酸アンモニウム５１０ｍｇを加え、室温で９時間撹拌した。溶媒を留去し、得られた残留物に６Ｎ塩酸３０ｍｌを加え８０℃で１．５時間撹拌した。溶媒を留去して得られた残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 ３９７ｍｇ（０．５９ｍｍｏｌ） 収率 ３４％
MS(ESI,m/z)440(MH+)
1H-NMR(DMSO-d6)δ:2.95(3H,s),3.25(3H,s),3.75(2H,dt),4.35(2H,t),4.20(2H,s,keto form),6.80(1H,s,enol form),7.38-7.48(2H,m),7.69(2H,d),8.04(2H,d),8.33(1H,d),8.95-9.40(7H,m),9.80(1H,br,enol form)
実施例２１４：Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］ベンズアミド 二トリフルオロ酢酸塩の合成
工程１ イミダゾリン−２−スルホン酸の合成
２−イミダゾリンチオン３．３２ｇ（３２．５ｍｍｏｌ）、ナトリウムモリブダート ２水和物２５０ｍｇ（１．０３ｍｍｏｌ）、塩化ナトリウム ７５０ｍｇを水１５ｍｌ中、氷冷下撹拌し、そこへ内温が４℃よりあがらないように３０％過酸化水素水２５ｍｌをゆっくり滴下した。滴下終了後２時間氷冷下撹拌した後、反応液を濾過して沈殿物を濾取し、冷水で洗浄後真空乾燥し、表題化合物を得た。
収量 １．４７ｇ（９．８１ｍｍｏｌ） 収率 ３０％
1H-NMR(DMSO-d6)δ:3.85(4H,s),10.35(1H,br)
工程２ ４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］安息香酸 エチルエステル トリフルオロ酢酸塩
４−アミノ安息香酸 エチル９９１ｍｇ（６．０ｍｍｏｌ）、イミダゾリン−２−スルホン酸１．０ｇ（６．６６ｍｍｏｌ）、トリエチルアミン１．３５ｇ（１３．３ｍｍｏｌ）をアセトニトリル３０ｍｌ中で一晩加熱環流した。溶媒を留去して得られる残留物を酢酸エチルで抽出し、１Ｎ 水酸化ナトリウム、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥溶媒を留去した。得られた残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 ８６ｍｇ（０．２５ｍｍｏｌ） 収率 ４％
1H-NMR(CD 3OD)δ:1.40(3H,t),3.80(4H,s),4.38(2H,q),7.38(2H,d),8.10(2H,d)
工程３ Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］ベンズアミド トリフルオロ酢酸の合成
４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］安息香酸 エチルエステル トリフルオロ酢酸塩８０ｍｇ（０．２３ｍｍｏｌ）を６Ｎ 塩酸１０ｍｌ中５時間加熱環流し、溶媒を留去して４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］安息香酸 塩酸塩を得た。
４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］安息香酸 塩酸塩 1H-NMR(DMSO-d6)δ:3.70(4H,s),7.40(2H,d),8.00(2H,d),8.60(2H,s)
得られたカルボン酸塩酸塩全量に、ジメチルホルムアミド２ｍｌ、３−（２−アミノエトキシ）ベンゾニトリル 塩酸塩（実施例１の工程３の化合物H-NMR(DMSO-d6)δ3.20(2H,t),4.25(2H,t),7.34(1H,d),7.46(1H,d),7.47(1H,s),7.54(1H,t),8.09(3H,br)）５０ｍｇ（０．２５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水）３４ｍｇ（０．２５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩４８ｍｇ（０．２５ｍｍｏｌ）、トリエチルアミン２５ｍｇ（０．２５ｍｍｏｌ）を加えて室温で一晩撹拌した。溶媒を減圧留去し、残留物に１Ｎ 水酸化ナトリウム水溶液を加え酢酸エチルで抽出した。飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥し溶媒を留去した。残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 ６７ｍｇ（０．１４ｍｍｏｌ） 収率６１％
1H-NMR(DMSO-d6)δ:3.65(2H,dt),3.70(4H,s),4.20(2H,t),7.30-7.52(6H,m),7.95(2H,d),8.50(2H,s),8.75(1H,t)
工程４ Ｎ−［２−（３−アミジノフェノキシ）エチル］−４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］ベンズアミド 二トリフルオロ酢酸の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−４−［（４，５−ジヒドロ−１Ｈ−イミダゾール−２−イル）アミノ］ベンズアミド トリフルオロ酢酸塩６６ｍｇ（０．１４ｍｍｏｌ）とエタノール０．５ｍｌを４Ｎ 塩化水素を含むジオキサン１０ｍｌ中で３日間撹拌した。溶媒を留去しエタノール１０ｍｌ、炭酸アンモニウム４５ｍｇを加え二日間撹拌し溶媒を留去した。残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 ５８ｍｇ（０．１０ｍｍｏｌ） 収率７１％
MS(ESI,m/z)367(MH+)
1H-NMR(DMSO-d6)δ:3.70(2H,dt),3.70(4H,s),4.20(2H,t),7.30-7.42(5H,m),7.54(1H,t),7.95(2H,d),8.60(2H,s),8.80(1H,t),9.19(2H,br),9.30(2H,br),10.90(1H,s)
実施例２１５：４−（３−アミジノフェノキシ）−３−（３Ｒ）−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］ブチル酸 二トリフルオロ酢酸塩の合成
工程１ ４−（３−シアノフェノキシ）−３−（３Ｒ）−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩の合成
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステル（実施例52の工程１の化合物）３．７ｇ（９．０ｍｍｏｌ）をジオキサン２０ｍｌ中撹拌し、そこへ４Ｎ 塩化水素を含むジオキサン１０ｍｌを加え室温で撹拌した。室温で２時間撹拌後、溶媒を留去して得られた残留物にジメチルホルムアミド２０ｍｌ、４−（Ｎ，Ｎ−ジメチルアミジノ）安息香酸 塩酸塩 ２．４７ｇ（１０．８ｍｌ）、１−ヒドロキシベンゾトリアゾール（含水）１．４６ｇ（１０．８ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩２．０７ｇ（１０．８ｍｍｏｌ）、トリエチルアミン３．７６ｍｌ（２７ｍｍｏｌ）を加え、室温で一晩撹拌した。反応液に酢酸エチルを加え１Ｎ 水酸化ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し溶媒を留去した。得られた残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 ２．０ｇ（３．３４ｍｍｏｌ） 収率３７％
1H-NMR(DMSO-d6)δ:2.85(2H,d),3.00(3H,s),3.25(3H,s),4.20(2H,m),4.75(1H,m),5.10(2H,s),7.28-7.52(9H,m),7.70(2H,d),8.02(2H,d),8.82(1H,d),9.06(1H,br),9.39(1H,br)
工程２ ４−（３−アミジノフェノキシ）−３−（３Ｒ）−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］ブチル酸 二トリフルオロ酢酸塩の合成
４−（３−シアノフェノキシ）−３−（３Ｒ）−［４−（Ｎ，Ｎ−ジメチルアミジノ）ベンゾイルアミノ］ブチル酸 トリフルオロ酢酸塩５１８ｍｇ（０．８７ｍｍｏｌ）を用いて実施例２１１の工程３と同様にして表題化合物を得た。
収量 ２０５ｍｇ（０．３２ｍｍｏｌ） 収率３７％
MS(ESI,m/z)412(MH+)
1H-NMR(DMSO-d6)δ:2.75(2H,d),2.95(3H,s),3.25(3H,s),4.10-4.30(2H,m),4.70(1H,m),7.32-7.43(3H,m),7.54(1H,t),7.71(2H,d),8.04(2H,d),8.80(1H,d),9.00(1H,br),9.15(2H,br),9.30(2H,br),9.35(1H,br)
実施例２１６：３−（３Ｒ）−［Ｎ−ベンジル−Ｎ−（４−アミジノベンゾイル）アミノ］−４−（３−アミジノフェノキシ）ブチル酸 二トリフルオロ酢酸塩の合成
工程１ ３−（３Ｒ）−ベンジルアミノ−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステルの合成
（３Ｒ）−３−アミノ−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステル 塩酸塩に１Ｎ 水酸化ナトリウム水溶液を加えジクロロメタンで抽出した。さらに飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥溶媒を留去して（３Ｒ）−３−アミノ−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステルを得た２４０ｍｇ（０．７７ｍｍｏｌ）をメタノール中撹拌し、そこへベンズアルデヒド１０６ｍｇ（１．０ｍｍｏｌ）、水素化シアノホウ素ナトリウム５８ｍｇ（０．９２ｍｍｏｌ）を加え室温で一晩撹拌した。１Ｎ 塩酸を加えてメタノールを減圧留去した後、１Ｎ 水酸化ナトリウムを加えて酢酸エチルで抽出、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、溶媒留去し表題化合物を得た。
収量 １９６ｍｇ（０．４９ｍｍｏｌ） 収率６４％
1H-NMR(CDCl3)δ2.70(2H,d),3.45(1H,m),3.85(2H,d),4.00(2H,m),5.15(2H,s),7.00-7.10(2H,m),7.20-7.40(12H,m)
工程２ ３−（３Ｒ）−［Ｎ−ベンジル−Ｎ−（４−シアノベンゾイル）アミノ］−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステルの合成
３−（３Ｒ）−ベンジルアミノ−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステル１９０ｍｇ（０．４７ｍｍｏｌ）、トリエチルアミン１５３ｍｇをジメチルホルムアミド５ｍｌ中撹拌し、そこへ氷冷下４−シアノベンゾイルクロリド７０ｍｇ（０．４７ｍｍｏｌ）を加え３時間撹拌した。１Ｎ 塩酸を加え酢酸エチルで抽出。１Ｎ水酸化ナトリウム、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、溶媒留去した後シリカゲルクロマトグラフィー（酢酸エチル−ヘキサン）で精製し表題化合物を得た。
収量 １４８ｍｇ（０．２８ｍｍｏｌ） 収率５９％
1H-NMR(CDCl3)δ2.50-3.30(2H,br),3.70-4.80(5H,br),5.15(2H,br),6.80-7.70(18H,br)
工程３ ３−（３Ｒ）−［Ｎ−ベンジル−Ｎ−（４−アミジノベンゾイル）アミノ］−４−（３−アミジノフェノキシ）ブチル酸 二トリフルオロ酢酸塩の合成
３−（３Ｒ）−［Ｎ−ベンジル−Ｎ−（４−シアノベンゾイル）アミノ］−４−（３−シアノフェノキシ）ブチル酸 ベンジルエステル１７８ｍｇ（０．３８ｍｍｏｌ）、エタノール１ｍｌを４Ｎ 塩化水素を含有するジオキサン５ｍｌ中で４日間撹拌した。溶媒を留去して得られた残留物にアンモニアを１０％含有する（ｗ／ｖ）エタノールを１０ｍｌ加え室温で５日間撹拌した。溶媒を留去し濃塩酸１０ｍｌを４０℃で一晩撹拌した。溶媒を留去し得られた残留物を逆相高速液体クロマトグラフィーにて、実施例２１１の工程３の精製と同様にして表題化合物を得た。
収量 ４８ｍｇ（０．０７ｍｍｏｌ） 収率１８％
MS(ESI,m/z)474(MH+)
1H-NMR(DMSO-d6)δ:2.60-3.00(2H,m),3.80-4.70(5H,m),7.10-8.00(13H,m),9.10-9.50(8H,br)
実施例２１７：Ｎ−［２−（３−アミジノフェノキシ）エチル］−３−（Ｅ）−（４−クロロフェニル）アクリルアミド トリフルオロ酢酸塩の合成
工程１ Ｎ−［２−（３−シアノフェノキシ）エチル］−３−（Ｅ）−（４−クロロフェニル）アクリルアミドの合成
３−（２−アミノエトキシ）ベンゾニトリル 塩酸塩１０９ｍｇ（０．５５ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（含水）８５ｍｇ（０．５５ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１０５ｍｇ（０．５５ｍｍｏｌ）、トリエチルアミン６１ｍｇ（０．６ｍｍｏｌ）、ｐ−クロロケイヒ酸１００ｍｇ（０．５５ｍｍｏｌ）を用いて実施例２１１の工程１と同様にして表題化合物を得た。
収量 １７０ｍｇ（０．５２ｍｍｏｌ） 収率９５％
1H-NMR(CDCl3)δ3.80(2H,dt),4.15(2H,t),6.05(1H,br),6.40(1H,d),7.15(1H,d),7.16(1H,s),7.27(1H,d),7.32ミ7.45(5H,m),7.61(1H,d)
工程２ Ｎ−［２−（３−アミジノフェノキシ）エチル］−３−（Ｅ）−（４−クロロフェニル）アクリルアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−３−（Ｅ）−（４−クロロフェニル）アクリルアミド１６５ｍｇ（０．５２ｍｍｏｌ）を用いて実施例１の工程６と同様にして表題化合物を得た。
収量 １０８ｍｇ（０．２４ｍｍｏｌ） 収率４６％
MS(ESI,m/z)344(MH+)
1H-NMR(DMSO-d6)δ:3.60(2H,dt),4.15(2H,t),6.70(1H,d),7.30-7.62(9H,m),8.40(1H,t),9.05(2H,br),9.30(2H,br)
実施例２１８：Ｎ−［２−（３−アミジノフェノキシ）エチル］−Ｎ−メチル−４−カルバモイル−ベンズアミド トリフルオロ酢酸塩の合成
実施例１１５の工程２の副生成物として表題化合物を得た。
収量 ２１ｍｇ（０．０５ｍｍｏｌ） 収率８％
MS(ESI,m/z)341(MH+)
1H-NMR(DMSO-d6)δ:3.00(3H,br),3.60-4.40(4H,br),7.20-8.10(10H,br),9.30(4H,br)
実施例２１９：１−（４−アミジノベンゾイル）−（２Ｒ）−２−［（３−アミジノフェノキシ）メチル］ピロリジン 二トリフルオロ酢酸塩の合成
工程１ １−ｔ−ブトキシカルボニル−（２Ｒ）−２−クロロメチルピロリジンの合成
（２Ｒ）−２−ヒドロキシメチル−ピロリジン５００ｍｇ（５ｍｍｏｌ）、ジ−ｔ−ブチルジカルボナート１．１ｇ（５ｍｍｏｌ）、トリエチルアミン５００ｍｇ（５ｍｍｏｌ）をジクロロメタン中、室温で一晩撹拌した。反応液を０．５Ｎ 塩酸、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥、溶媒留去した。残留物をジクロロメタン２０ｍｌに溶解しトリエチルアミン７６０ｍｇ（７．５ｍｍｏｌ）、メシルクロライド８６０ｍｇ（７．５ｍｍｏｌ）を０℃で加え、室温で５時間撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理して得た残留物をジメチルホルムアミド５ｍｌに溶解し塩化リチウム１．０６ｇ（２５ｍｍｏｌ）を加え６５℃で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量 ４２６ｍｇ（１．９４ｍｍｏｌ） 収率 ３９％
1H-NMR(CDCl3)δ1.50(9H,s),1.75-2.05(4H,m),3.30-3.80(4H,m),4.00(1H,m)
工程２ １−ｔ−ブトキシカルボニル−（２Ｒ）−２−［（３−シアノフェノキシ）メチル］ピロリジンの合成
１−ｔ−ブトキシカルボニル−（２Ｒ）−２−クロロメチルピロリジン４３０ｍｇ（２ｍｍｏｌ）をジメチルアミド５ｍｌに溶解し、３−ヒドロキシベンゾニトリル２３８ｍｇ（２ｍｍｏｌ）、ヨウ化カリウム５００ｍｇ（３ｍｍｏｌ）、炭酸カリウム４１４ｍｇ（３ｍｍｏｌ）を加え、９０℃で３日間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理して得た残留物をシリカゲルクロマトグラフィーで精製し表題化合物を得た。
収量 ７３ｍｇ（０．２４ｍｍｏｌ） 収率 １２％
1H-NMR(CDCl3)δ1.45(9H,s),1.82-2.08(4H,m),3.40(2H,br),3.90(1H,m),4.18(2H,br),7.10-7.30(3H,m),7.35(1H,t)
工程３ １−（４−シアノベンゾイル）−（２Ｒ）−２−［（３−シアノフェノキシ）メチル］ピロリジンの合成
１−ｔ−ブトキシカルボニル−（２Ｒ）−２−［（３−シアノフェノキシ）メチル］ピロリジン７０ｍｇ（０．２３ｍｍｏｌ）を４Ｎ塩化水素を含むジオキサン溶液に溶解し室温で３時間撹拌した。溶媒を留去して脱ｔ−ブトキシカルボニル体の粗生成物を得た。４−シアノ安息香酸３８ｍｇ（０．２５ｍｍｏｌ）をジメチルホルムアミド３ｍｌに溶解し、Ｎ−メチルモルホリン１００ｍｇ（１ｍｍｏｌ）、クロロ蟻酸エチル２５ｍｇ（０．２３ｍｍｏｌ）を加え０℃で５分間撹拌し、そこへ脱ｔ−ブトキシカルボニル体の粗生成物を加え室温で２時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理して表題化合物を得た。
収量 ６９．６ｍｇ（０．２１ｍｍｏｌ） 収率 ９１％
1H-NMR(CDCl3)δ:1.82-2.22(4H,m),3.38-3.55(2H,m),4.10-4.63(3H,m),7.18-7.30(3H,m),7.39(1H,t),7.58(2H,d),7.73(2H,d)
工程４ １−（４−アミジノベンゾイル）−（２Ｒ）−２−［（３−アミジノフェノキシ）メチル］ピロリジン 二トリフルオロ酢酸塩の合成
１−（４−シアノベンゾイル）−（２Ｒ）−２−［（３−シアノフェノキシ）メチル］ピロリジン６９ｍｇ（０．２１ｍｍｏｌ）を出発原料とし、実施例１の工程６と同様の操作により表題化合物を得た。
収量 ２２．７ｍｇ（０．０３８ｍｍｏｌ） 収率 １８％
MS(ESI,m/z)366(MH+)
1H-NMR(DMSO-d6)δ:1.80-2.20(4H,m),3.30-3.55(2H,m),4.20-4.55(3H,m),7.36-7.58(4H,m),7.70(2H,d),7.89(2H,d),9.27-9.47(8H,m)
実施例２２０：Ｎ−［２−（３−アミジノフェノキシ）エチル］−６−（ピロリジン−１−イル）ニコチンアミド トリフルオロ酢酸塩の合成
工程１ ５−ブロモ−２−（ピロリジン−１−イル）ピリジンの合成
２−アミノ−５−ブロモピリジン ４．９５ｇ（２８．６ｍｍｏｌ）をトルエン４０ｍｌに溶解し、ジイソプロピルエチルアミン９．９５ｍｌ（５７．２ｍｍｏｌ）、１、４−ジブロモブタン６．１５ｇ（２８．６ｍｍｏｌ）、４−（ジメチルアミノ）ピリジン１００ｍｇ（０．８２ｍｍｏｌ）を加え三晩撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 ２．６ｇ（１１．１ｍｍｏｌ） 収率 ３９％
1H-NMR(CDCl3)δ:1.91-2.05(4H,m),3.32-3.46(4H,m),6.22(1H,d),7.44(1H,dd),8.12(1H,d)
工程２ ６−（ピロリジン−１−イル）ニコチン酸 メチルエステルの合成
５−ブロモ−２−（ピロリジン−１−イル）ピリジン２．６ｇ（１１．１ｍｍｏｌ）をジメチルホルムアミド３０ｍｌに溶解し、メタノール８．９ｍｌ（２２０ｍｍｏｌ）、トリエチルアミン３．０６ｍｌ（２２ｍｍｏｌ）、酢酸パラジウム（II）１２４ｍｇ（０．５ｍｍｏｌ）、トリフェニルフォスフィン２．７ｇ（１１．１ｍｍｏｌ）を加え一酸化炭素存在下７０℃で一晩撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し粗製物を得た。続いてシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量 １．０ｇ（４．８５ｍｍｏｌ） 収率 ４４％
1H-NMR(CDCl3)δ1.94-2.07(4H,m),3.40-3.56(4H,m),3.82(3H,s),6.29(1H,d),7.94(1H,dd),8.77(1H,d)
工程３ ６−（ピロリジン−１−イル）ニコチン酸の合成
６−（ピロリジン−１−イル）ニコチン酸 メチルエステル１．０ｇ（４．８５ｍｍｏｌ）を濃塩酸１０ｍｌに溶解し４０℃で一晩撹拌した。溶媒を留去し、表題化合物の塩酸塩を得た。
収量 １．０ｇ（４．３９ｍｍｏｌ） 収率 ９０％
工程４ Ｎ−［２−（３−アミジノフェノキシ）エチル］−６−（ピロリジン−１−イル）ニコチンアミド トリフルオロ酢酸塩の合成
６−（ピロリジン−１−イル）ニコチン酸３９６ｍｇ（１．７４ｍｍｏｌ）をジクロロメタン１０ｍｌに溶解し、トリエチルアミン０．８６ｍｌ（６．１８ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール３０６ｍｇ（２．２７ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩４３３ｍｇ（２．２７ｍｍｏｌ）、３−（２−アミノエトキシ）ベンゾニトリル 塩酸塩４４９ｍｇ（２．２７ｍｍｏｌ）を加え室温で一晩撹拌した。ジクロロメタンを抽出溶媒とし常法に従って処理し、縮合体粗製物を得た。得られた粗製物をエタノール１ｍｌ、４規定塩化水素のジオキサン溶液５ｍｌに溶解し三晩撹拌した。溶媒を留去後、エタノール５ｍｌに溶解させ、炭酸アンモニウム６６１ｍｇ（８．４９ｍｍｏｌ）を加え一晩撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ４３０ｍｇ（０．７４ｍｍｏｌ） 収率 ４３％
MS(ESI,m/z)354(MH+)
1H-NMR(DMSO-d6)δ:1.91-2.05(4H,m),3.44-3.58(4H,m),3.63(2H,dt),4.33(2H,t),6.80(1H,d),7.29-7.42(3H,m),7.54(1H,dd),8.12(1H,dd),8.51(1H,d),8.73(1H,t),9.20(2H,br),9.29(2H,br)
実施例２２１：（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−［（１−アセトイミドイルピペリジン−４−イル）メチル］ベンゾイルアミノ］ブチル酸 二トリフルオロ酢酸塩の合成
（３Ｒ）−４−（３−アミジノフェノキシ）−３−［４−［（ピペリジン−４−イル）メチル］ベンゾイルアミノ］ブチル酸エチル 二トリフルオロ酢酸塩（ＪＰ２ ５２−３）１０ｍｇ（０．０２ｍｍｏｌ）をエタノール１ｍｌに溶解させ、エチルアセトイミダート塩酸塩１０ｍｇ（０．０８ｍｍｏｌ）、トリエチルアミン０．５ｍｌ（３．３ｍｍｏｌ）を加え、室温で一晩撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量 ６ｍｇ（０．００８ｍｍｏｌ） 収率 ５７％
MS(ESI,m/z)480(MH+)
1H-NMR(DMSO-d6)δ:1.10-1.35(2H,m),1.58-1.75(2H,m),1.82-1.97(1H,m),2.23(3H,s),2.58(2H,d),2.70(2H,d),2.95-3.21(2H,m),3.62-3.92(1H,m),3.98-4.13(2H,m),4.24(1H,dd),4.68(1H,ddt),7.27(2H,d),7.32-7.43(3H,m),7.53(1H,dd),7.80(2H,d),8.47-8.65(2H,m),9.05(1H,br),9.21(2H,br),9.27(2H,br)
実施例２２２：（３Ｒ）−４−（３−アミジノフェノキシ）−３−［［４−［イミノ（ピロリジン−１−イル）メチル］ベンゾイル］アミノ］ブチル酸 二塩酸塩
工程１ ４−［イミノ（ピロリジン−１−イル）メチル］安息香酸 塩酸塩の合成
４−シアノ安息香酸１５．２ｇ（１０３ｍｍｏｌ）を４規定塩化水素を含む酢酸エチル溶液２００ｍｌ、エタノール５０ｍｌの溶液に加え５日間撹拌した。溶媒を減圧留去後、得られた固体に酢酸エチル１００ｍｌを加え３０分撹拌した後、固体を濾取した。得られた固体をエタノール１００ｍｌを溶媒としてピロリジン１５．０ｇ（２１１ｍｍｏｌ）およびトリエチルアミン１０．０ｇ（９８．８ｍｍｏｌ）と２日間反応させた。溶媒を留去後６規定塩酸４０ｍｌを加え８５℃で４時間反応させた。溶媒を留去後１規定塩酸５０ｍｌを加え３０分撹拌した後、固体を濾取し、さらに氷水２０ｍｌで洗浄した。減圧下乾燥して表題化合物を得た。
収量７．６７ｇ（３０．１ｍｍｏｌ） 収率 ２９．２％
MS(ESI,m/z)479(MH+)
1H-NMR(DMSO-d6)δ:1.78-1.92(2H,m),1.98-2.12(2H,m),3.23-3.43(2H,m),3.58-3.62(2H,m),7.78(2H,d),8.15(2H,d),9.18(1H,bs),9.45(1H,bs)13.41(1H,bs)
工程２ （３Ｒ）−４−（３−アミジノフェノキシ）−３−［［４−［イミノ（ピロリジン−１−イル）メチル］ベンゾイル］アミノ］ブチル酸 二トリフルオロ酢酸塩の合成
（３Ｒ）−３−ｔ−ブトキシカルボニルアミノ−４−（３−シアノフェノキシ）ブチル酸ベンジル（ＪＰ２ ５２−１）３．５２ｇ（８．５８ｍｍｏｌ）を４規定塩化水素を含む酢酸エチル溶液５０ｍｌに溶解し、室温で４時間撹拌した。溶媒を留去して得られた得られた固体をジメチルホルムアミド９５ｍｌとジメチルスルホキシド２０ｍｌの混合溶媒に溶解し、４−［イミノ−（ピロリジン−１−イル）−メチル］安息香酸 塩酸塩１．７４ｇ（６．８３ｍｍｏｌ）、ブロモトリスピロリジノホスホニウムヘキサフルオロボラート２．７１ｇ（５．８１ｍｍｏｌ）およびジイソプロピルエチルアミン３．８５ｇ（８．２６ｍｍｏｌ）を加え室温で終夜撹拌した。酢酸エチル４００ｍｌを加え、１規定水酸化ナトリウム水溶液２００ｍｌで洗浄し、有機層を分層、硫酸マグネシウムで乾燥した。溶媒を留去して得られた粗製物を逆相クロマトグラフィーに付し、０．１％トリフルオロ酢酸を含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより縮合体を得た。この縮合体を４規定塩化水素を含むジオキサン溶液３５ｍｌとエタノール７ｍｌで終夜反応させた。溶媒を留去して得られた残留物をエタノール２０ｍｌに溶解し、炭酸アンモニウム６２０ｍｇ（６．５９ｍｍｏｌ）を加え終夜で反応させた。さらに溶媒を留去して得られた残留物を６規定塩酸、４０℃で終夜反応させた。溶媒を留去して得られた得られた残留物を逆相クロマトグラフィーに付し、０．１％トリフルオロ酢酸を含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出した。目的物のフラクションを凍結乾燥し、４Ｎ 塩化水素を含むジオキサン２５ｍｌを加えて３０分撹拌した。溶媒を留去し、そこへ２５ｍｌの水を加え凍結乾燥して表題化合物を得た。
収量３０１ｍｇ（０．５９０ｍｍｏｌ） 収率 ６．９％
MS(ESI,m/z)438(MH+)
1H-NMR(DMSO-d6)δ:1.80-1.91(2H,m),2.02-2.11(2H,m),2.73(2H,d)3.35(2H,t),3.57(2H,d),4.13(1H,dd),4.22(1H,dd),4.70(1H,ddt),7.34(1H,d),7.38-7.45(2H,m),7.53(1H,dd),7.74(2H,d),8.04(2H,d),8.83(1H,d),8.93(1H,bs),9.32(2H,bs),9.34(2H,bs),9.38(1H,bs),12.42(1H,bs)
実施例２２３：Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−ベンジルエチル］−４−（ピロリジン−１−カルボニル）ベンズアミド トリフルオロ酢酸塩の合成
工程１ Ｎ−［（１Ｒ）−１−ベンジル−２−クロロエチル］カルバミン酸 ｔ−ブチルの合成
Ｄ−フェニルアラニン６．０１ｇ（３６．４ｍｍｏｌ）をトリエチルアミン５．３５ｇ（５３．０ｍｍｏｌ）、テトラヒドロフラン５０ｍｌおよび水５０ｍｌの溶液に溶解した後、ジ−ｔ−ブチルジカーボナート７．５２ｇ（３４．５ｍｍｏｌ）を加え室温で終夜撹拌し、Ｎ−ｔ−ブトキシカルボニル化を行った。常法に従って処理して得られた固体をＴＨＦ８０ｍｌに溶解し、クロロ蟻酸エチル３．９７ｇ（３６．６ｍｍｏｌ）、ジイソプロピルエチルアミン６．４７ｇ（５０．１ｍｍｏｌ）および水素化ホウ素ナトリウム２．１２ｇ（５６．０ｍｍｏｌ）を用いて還元した。続いてメタンスルフォニルクロライド４．１７ｇ（３６．４ｍｍｏｌ）、ジイソプロピルエチルアミン６．４７ｇ（５０．１ｍｍｏｌ）を用いジメチルホルムアミド８０ｍｌを溶媒として反応させた。常法に従って処理して得られた残留物を塩化リチウム８．４２ｇ（１９９ｍｍｏｌ）、ジメチルホルムアミド１２０ｍｌを用い４０℃終夜で反応させ常法に従って処理し表題化合物を得た。
収量８．５２ｇ（３１．６ｍｍｏｌ） 収率 ８６．８％
1H-NMR(CDCl3)δ:2.82-2.94(2H,m),3.45(1H,dd),3.61(1H,dd),4.02-4.20(1H,m),4.85(1H,d),7.15-7.38(5H,m)
工程２ Ｎ−［（１Ｒ）−１−ベンジル−２−（３−シアノフェノキシ）エチル］カルバミン酸 ｔ−ブチルの合成
Ｎ−［（１Ｒ）−１−ベンジル−２−クロロエチル］カルバミン酸 ｔ−ブチル８．５２ｇ（３１．６ｍｍｏｌ）、炭酸カリウム１２．１ｇ（８７．５ｍｍｏｌ）および３−シアノフェノール５ｇ（４１．９ｍｍｏｌ）をジメチルホルムアミド１２０ｍｌを溶媒とし７０℃で終夜反応させた。常法に従って処理しシリカゲルカラムクロマトグラフィーで精製し表題化合物を得た。
収量５．２８ｇ（１５．０ｍｍｏｌ） 収率 ４７．５％
1H-NMR(CDCl3)δ:1.42(9H,s),2.95-3.02(2H,m),3.90(2H,t),4.85(1H,d),7.08-7.41(9H,m)
工程３ Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−ベンジルエチル］−４−（ピロリジン−１−カルボニル）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［（１Ｒ）−１−ベンジル−２−（３−シアノフェノキシ）エチル］カルバミン酸 ｔ−ブチル６３０ｍｇ（１．７９ｍｍｏｌ）を用い、４規定塩化水素を含むジオキサン溶液１０ｍｌで処理し、脱保護体を得た。４−（ピロリジン−１−カルボニル）安息香酸 ７２０ｍｇ（３．２８ｍｍｏｌ）、１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩１．５５ｇ（８．０９ｍｍｏｌ）１−ヒドロキシベンゾトリアゾール１．２１ｇ（８．９５ｍｍｏｌ）およびジイソプロピルエチルアミン１．４８ｇ（１１．５ｍｍｏｌ）、４−ジメチルアミノピリジン５２ｍｇを用いジメチルホルムアミド中で縮合した。さらに縮合体を４規定塩化水素を含むジオキサン溶液２０ｍｌとエタノール２ｍｌで６日間反応させた。溶媒を留去して得られた残留物をエタノール２０ｍｌに溶解し、炭酸アンモニウム１．０ｇ（１０．６ｍｍｏｌ）を加え４日間反応させた。溶媒を留去して得られた残留物を逆相クロマトグラフィーに付し、０．１％トリフルオロ酢酸を含有する（ｖ／ｖ）水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥して表題化合物を得た。
収量３２５ｍｇ（０．５５６ｍｍｏｌ） 収率 ３１．１％
1H-NMR(DMSO-d6)δ:1.75-1.93(4H,m),2.92-3.15(2H,m),3.35(2H,t),3.44(2H,t),4.05-4.12(2H,m),4.48-4.60(1H,m),7.18-7.55(9H,m),7.58(2H,d),7.82(2H,d),8.62(1H,d),9.15(2H,bs),9.27(2H,bs)
実施例２２４：Ｎ−［（１Ｒ）−２−（３−アミジノフェノキシ）−１−ベンジルエチル］−４−（Ｎ，Ｎ−ジメチルカルバモイル）ベンズアミド トリフルオロ酢酸塩の合成
Ｎ−［（１Ｒ）−１−ベンジル−２−（３−シアノフェノキシ）エチル］カルバミン酸 ｔ−ブチル６３０ｍｇ（１．７９ｍｍｏｌ）、４−（Ｎ，Ｎ−ジメチルカルバモイル）安息香酸を用い、実施例２２３の工程３記載と同様の方法に従って表題化合物を得た。
収量４１７ｍｇ（０．７４７ｍｍｏｌ） 収率 ４１．７％
1H-NMR(DMSO-d6)δ:2.84(3H,s),3.00(3H,s),2.95-3.10(2H,m),3.10-3.22(2H,m),4.50-4.62(1H,m),7.18-7.60(9H,m),7.46(2H,d),7.82(2H,d),8.62(1H,d),9.15(2H,bs),9.27(2H,bs)
実施例２２５：Ｎ−［２−（３−アミジノフェノキシ）エチル］−１−（ジメチルアミノカルボニル）ピペリジン−４−カルボキシアミド トリフルオロ酢酸塩の合成
工程１ Ｎ−［２−（３−シアノフェノキシ）エチル］−１−（ジメチルアミノカルボニル）ピペリジン−４−カルボキシアミドの合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−ピペリジン−４−カルボキシアミド（ＪＰ２ １９−１）４３０ｍｇ（１．５８ｍｍｏｌ）をジメチルホルムアミド１．６ｍｌに溶解し、トリエチルアミン０．３ｍｌ（２．０６ｍｍｏｌ）、ジメチルカルバモイルクロライド０．１６ｍｌ（１．７４ｍｍｏｌ）を０℃で加え、室温下２時間撹拌した。酢酸エチルを抽出溶媒とし常法に従って処理し表題化合物を得た。
収量２０６ｍｇ（０．６０ｍｍｏｌ） 収率 ３８％
工程２ Ｎ−［２−（３−アミジノフェノキシ）エチル］−１−（ジメチルカルバモイル）ピペリジン−４−カルボキシアミド トリフルオロ酢酸塩の合成
Ｎ−［２−（３−シアノフェノキシ）エチル］−１−（ジメチルアミノカルボニル）ピペリジン−４−カルボキシアミド２０６ｍｇ（０．６０ｍｍｏｌ）を４規定塩化水素を含むジオキサン３ｍｌ中撹拌し、そこへ塩化水素を含むエタノール３ｍｌを加えて室温で１日間撹拌後、溶媒を減圧留去して得た残留物をアンモニアを10％含有する（ｗ／ｖ）エタノール溶液５ｍｌに溶解して室温で１日間撹拌した。溶媒を留去して得られた残留物をオクタドデシル基化学結合型シリカゲルを充填剤とする逆相高速液体クロマトグラフィーに付し、トリフルオロ酢酸を０．１％含有する（ｖ／ｖ）、水とアセトニトリルの混合溶媒で溶出し、目的物のフラクションを凍結乾燥することにより、表題化合物を得た。
収量１６０ｍｇ（０．３４ｍｍｏｌ） 収率 ５６％
MS(ESI,m/z)362(MH+)
1H-NMR(DMSO-d6)δ:1.50(2H,ddd),1.65(2H,dd),2.30(1H,tt),2.65(2H,d),2.70(6H,s),3.47(2H,dd),3.52(2H,d),4.08(2H,t),7.30(1H,d),7.36(1H,s),7.38(1H,d),7.53(1H,t),8.09(1H,t),9.24(4H,d)
実施例２２６
活性化血液凝固第Ｘ因子阻害活性の測定を実施例９３と同様にして、又、トロンビン阻害活性の測定の測定を実施例９４にして行った。
又、抗血液凝固活性の測定を実施例１８４と同様にして行った。結果をまとめて表−３に示す。
Figure 0004103147
但し、表中、実施例１８１の化合物は（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブタン酸 トリフルオロ酢酸塩を示す。
この結果より本発明のベンズアミジン誘導体は、活性化血液凝固第Ｘ因子に特異的な高い阻害活性を示すことがわかる。
以下、実施例１８５以降の本発明の化合物の構造式を示す。
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
本発明化合物又はその塩を有効成分とする抗凝固剤は優れた活性化血液凝固第Ｘ因子阻害作用に基づく抗血液凝固作用を示す。従って、本発明化合物は脳梗塞、脳血栓、脳塞栓、一過性脳虚血発作（ＴＩＡ）、くも膜下出血（血管れん縮）等の脳血管障害における疾病、急性及び慢性心筋梗塞、不安定狭心症、冠動脈血栓溶解等の虚血性心疾患における疾病、肺梗塞、肺塞栓等の肺血管障害における疾病、末梢動脈閉塞症、深部静脈血栓症、汎発性血管内凝固症候群、さらに人工血管術及び人工弁置換後の血栓形成、冠動脈バイパス術後における再閉塞及び再狭窄、経皮的経管式冠動脈形成術（ＰＴＣＡ）または経皮的経管式冠動脈再開通療法（ＰＴＣＲ）等の血行再建後の再閉塞及び再狭窄、体外循環時の血栓形成などの予防・治療剤として利用できる。Background of the Invention
The present invention is caused by a novel orally administrable benzamidine derivative that reversibly inhibits activated blood coagulation factor X and exhibits a strong anticoagulant action, and a blood coagulation inhibitor or thrombus or embolus containing them as an active ingredient The present invention relates to a preventive / therapeutic agent for diseases. Examples of the diseases to be applied include diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vascular spasm), acute and chronic myocardial infarction Diseases in ischemic heart diseases such as heart disease, coronary artery thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, and artificial vascular surgery Revascularization such as thrombus formation after prosthetic valve replacement, reocclusion and restenosis after coronary artery bypass grafting, percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary artery recurrent therapy (PTCR) Later reocclusion and restenosis, thrombus formation during extracorporeal circulation, and the like.
Thromboembolic diseases such as myocardial infarction, cerebral thrombosis, and peripheral arterial thrombosis tend to increase year by year as the lifestyles become westernized and the population ages, and the social importance of treatment is increasing It is growing. Anticoagulant therapy is part of a medical therapy in the treatment and prevention of thrombosis along with fibrinolysis and antiplatelet therapy.
Conventionally, antithrombin agents have been developed as thrombus formation inhibitors, but thrombin not only controls the activation of fibrinogen, which is the final stage of the coagulation reaction, but also deeply activates and aggregates platelets. Because of its involvement, its inhibition was known to be at risk of bleeding tendency. In addition, the bioavailability of oral administration is low, and no thrombin inhibitor that can be administered orally has been marketed.
Activated blood coagulation factor X is located at the confluence of extrinsic and intrinsic coagulation cascade reactions and is located upstream of thrombin, so that inhibition of this factor is more efficient and specific than thrombin inhibition Possible inhibition of the system [THROMBOSIS RESEARCH 19: 339-349, 1980].
Disclosure of the invention
An object of the present invention is to provide a compound having an excellent activated blood coagulation factor X inhibitory action.
An object of the present invention is to provide a compound having an inhibitory action specific to activated blood coagulation factor X that can be administered orally.
The present invention is to provide an anticoagulant or a prophylactic / therapeutic agent for thrombus or embolus containing the above compound.
As a result of various studies in view of the above situation, the present inventors have shown that a specific novel benzamidine derivative has an excellent activated blood coagulation factor X inhibitory action, and various diseases based on thrombus / embolism The present invention has been found to be useful as a preventive and therapeutic agent for the above, and the present invention has been completed. That is, the present invention is a benzamidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, and an anticoagulant containing them as an active ingredient.
Figure 0004103147
[In the general formula (1), L represents an organic group of any one of the following formulas (2) to (5).
Figure 0004103147
(Wherein, in formulas (2), (3) and (5), W represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 4 to 10 carbon atoms, an aralkyl group having 5 to 12 carbon atoms or a carbon number. 2 to 4 carboxylalkylsulfonyl groups, wherein in formula (3), either D or D ′ represents a bond to Y in general formula (1), the other represents a hydrogen atom,
In the formula (2), X represents a hydrogen atom, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a methyl, ethyl or benzyl group which may have a substituent. Are a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, an amidinopiperidyloxy group, an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, and a carbon number of 8 -14 alkoxycarbonylpiperidyloxy group, C6-8 piperidylalkyl group, C8-11 iminoalkylpiperidylalkyl group, C9-15 alkoxycarbonylpiperidylalkyl group, pyrrolidyloxy group, carbon number 6-9 iminoalkylpyrrolidyloxy groups, 7 carbon atoms 13 alkoxycarbonyl pyrrolidyl group, amidino group, hydroxy group, halogeno group, an alkyl group of indolyl group or C1-5 and the like. In formula (2), X and W may combine to form a ring, and in this case, -W-X- represents an ethylene group, trimethylene group or tetramethylene group. )
When L is an organic group represented by formula (2) or (3), V is a hydrogen atom, a phenyl or benzoyl group having a substituent, an optionally substituted benzenesulfonyl, or 2-naphthalenesulfonyl. , Camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, pyridinecarbonyl, phenylthiocarbonyl or benzimidoyl group or an optionally substituted carbon number 1-6 alkanesulfonyl groups are shown.
When L is an organic group of the formula (4), V is a benzoyl group having a substituent, an optionally substituted 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidini A ruaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, phenylthiocarbonyl or benzimidoyl group or an alkanesulfonyl group having 1 to 6 carbon atoms which may have a substituent is shown. When L is an organic group of the formula (5), V represents an aryl group having 4 to 10 carbon atoms which may have a substituent.
In the case where L is an organic group of any one of formulas (2) to (5), the substituent in the case where V has a substituent includes a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, carbon A mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an amidino group, a mono- or dialkylamidino group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms which may be substituted with an alkoxy group having 1 to 3 carbon atoms, halogeno Group, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, arylamino group having 4 to 6 carbon atoms, alkoxycarbonylamino group having 2 to 7 carbon atoms, aminoalkyl group having 1 to 3 carbon atoms, carbon number 2 to 7 mono- or dialkylaminoalkyl group, 4 to 10 carbon atoms N-alkyl-N-alkoxycarbonylaminoalkyl group, piperidyloxy group, C6-C9 acylpiperidyloxy group, C7-C10 iminoalkylpiperidyloxy group, C8-C14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, carbon number which may be substituted with mino group 6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C2-7 hydroxycarbonylalkyl group, C3-8 alkoxycarbonylalkyl group, C3-3 7 hydroxycarbonyl alkenyl group, C 4-8 alkoxycarbonyl alkenyl group, C 4-10 aryl group, C 6-12 aryl alkenyl group, C 1-10 alkoxy group, nitro group, tri Fluoromethyl group, alkyl group having 3 to 8 carbon atoms, arylsulfur having 4 to 10 carbon atoms Nyl group, arylalkyl group having 5 to 12 carbon atoms, piperazinecarbonyl group, iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, benzylsulfonylamino group, C6-C9 piperidylalkyl group, C8-C12 iminoalkylpiperidylalkyl group, C6-C9 piperididenealkyl group, C8-C12 iminoalkylpiperididenealkyl group, guanidino group , Phosphono group, dialkoxyphosphoryl group having 2 to 9 carbon atoms, monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, aminoethyloxy group, dialkylaminosulfonyl group having 3 to 6 carbon atoms, dialkyl having 2 to 4 carbon atoms A guanidino group is mentioned.
When L is an organic group of any one of formulas (2) to (4), or V represents an organic group of the following formula (6).
Figure 0004103147
(R 1 Represents a hydrogen atom, an alkoxycarbonyl group or a methyl group, and R 2 Represents a hydrogen atom, a methyl group, a butyl group, a benzyl group, an aminobutyl group, a hydroxycarbonylethyl group, a hydroxycarbonylpropyl group or an imidazolylmethyl group; Three Represents a hydrogen atom or a pyridyl group. )
Y represents one of the following formulas (7), (8), (9), (10) or (11).
Figure 0004103147
(In formulas (7) and (8), n represents an integer of 1 to 3)
Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, or any one of the following formulas (12-1), (12-2), and (12-3).
Figure 0004103147
(R Four Is either a carboxyl group or an aryl group having 4 to 10 carbon atoms, R Five Is an alkyl group having 1 to 6 carbon atoms, R 6 Is either a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 7 carbon atoms, R 7 Represents either a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ]]
BEST MODE FOR CARRYING OUT THE INVENTION
As the compound of the general formula (1), the following compounds are preferable.
In general formula (1), L represents an organic group of any one of formulas (2) to (5), and in formula (2), W is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or 4 carbon atoms. 10 represents an aryl group having 10 to 10 carbon atoms or an aralkyl group having 5 to 12 carbon atoms, W in formulas (3) and (5) represents a hydrogen atom, and in formula (3), D represents Y in formula (1). D ′ represents a hydrogen atom,
X represents a hydrogen atom, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a methyl, ethyl or benzyl group which may have a substituent, and the substituent in the case of having a substituent includes a carboxyl group, carbon An alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, an alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, and a carbon number 6-8 piperidylalkyl groups, C8-11 iminoalkylpiperidylalkyl groups, C9-15 alkoxycarbonylpiperidylalkyl groups, pyrrolidyloxy groups, C6-9 iminoalkylpyrrolidyloxy groups, C7-13 alkoxycarbonylpyrrolidyloxy Group, amidino group, hydroxy group, halogeno group, indolyl group or alkyl group having 1 to 3 carbon atoms, and in formula (2), X and W may be combined to form a ring. -W-X- represents an ethylene group, trimethylene group or tetramethylene group;
When L is an organic group of either formula (2) or (3), V is a hydrogen atom, a benzoyl group having a substituent, an optionally substituted benzenesulfonyl, 2-naphthalenesulfonyl, camphor Sulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, phenylthiocarbonyl or benzimidoyl group or an optionally substituted alkane having 1 to 6 carbon atoms Represents a sulfonyl group,
When L is an organic group of the formula (4), V is a benzoyl group having a substituent, an optionally substituted 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidini A ruaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, phenylthiocarbonyl or benzimidoyl group or an optionally substituted alkanesulfonyl group having 1 to 6 carbon atoms, wherein L is an organic group of the formula (5) In the case of a group, V represents an optionally substituted aryl group having 4 to 10 carbon atoms,
In the case where L is an organic group of any one of formulas (2) to (5), the substituent in the case where V has a substituent includes a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, carbon C2-C7 mono- or dialkylcarbamoyl group, amidino group, C2-C7 mono- or dialkylamidino group, C1-C8 acyl group, halogeno group, amino group, C1-C6 mono- or dialkyl Amino group, arylamino group having 4 to 6 carbon atoms, alkoxycarbonylamino group having 2 to 7 carbon atoms, aminoalkyl group having 1 to 3 carbon atoms, mono- or dialkylaminoalkyl group having 2 to 7 carbon atoms, carbon number 4 -10 N-alkyl-N-alkoxycarbonylaminoalkyl group, piperidyloxy group, C7-10 iminoalkylpiperidyloxy Group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, C6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C3-7 Hydroxycarbonylalkyl group, C4-8 alkoxycarbonylalkyl group, C2-7 hydroxycarbonylalkenyl group, C3-8 alkoxycarbonylalkenyl group, C4-10 aryl group, carbon number 6-12 arylalkenyl groups, C1-C10 alkoxy groups, nitro groups, trifluoromethyl groups, C3-C8 alkyl groups, C4-C10 arylsulfonyl groups, C5-C12 Arylalkyl group, piperazine carbonyl group, iminoalkyl piperazine having 7 to 10 carbon atoms Rubonyl group, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl group having 6-9 carbon atoms, benzylsulfonylamino group, piperidylalkyl group having 6-9 carbon atoms, iminoalkylpiperidylalkyl group having 8-12 carbon atoms, 6-6 carbon atoms 9 piperididenealkyl groups, C8-12 iminoalkylpiperididenealkyl groups, guanidino groups, phosphono groups, C2-9 dialkoxyphosphoryl groups, C1-4 monoalkoxyhydroxyphosphoryl groups An aminoethyloxy group,
When L is an organic group of any one of formulas (2) to (4), or V represents an organic group of formula (6),
Y represents any one of the formulas (7), (8), (9), (10) or (11), and in the formula (7), n is 1 or 2, and in the formula (8), n is 1 and
Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group or formula (12-1), and in formula (12-1), R Four Is preferably a benzamidine derivative or a pharmaceutically acceptable salt thereof, which represents either a carboxyl group or an aryl group having 4 to 10 carbon atoms.
Here, in the general formula (1), when V has a substituent, the substituent is carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, carbamoyl group, amidino group, acetyl group, bromine atom, amino group, methylamino Group, t-butoxycarbonylamino group, aminomethyl group, (methylamino) methyl group, (Nt-butoxycarbonyl-N-methylamino) methyl group, 4-piperidyloxy group, 1-acetimidoyl-4- Piperidyloxy group, 3-pyrrolidyloxy group, 1-t-butoxycarbonyl-3-pyrrolidyloxy group, 2-carboxyl ethenyl group, 2- (ethoxycarbonyl) ethenyl group, dimethylcarbamoyl group, N-ethyl-N -Methylcarbamoyl group, 2-imidazolinyl group, 1-piperidinecarbonyl group, N, N-dimethyl Midino group, 2- (tetrahydropyrimidinyl) group, 1-pyrrolidinecarbonyl group, 2- (4-pyridyl) vinyl group, 1-pyrrole group, cyclohexyloxy group, diethylamino group, 2- (4-pyridyl) ethyl group, isopropyl Group, 1-pyrrolidyl group, benzoyl group, benzenesulfonyl group, benzyl group, 4-pyridyl group, dimethylamino group, 1-piperidinyl group, phenoxy group, 1-piperazinecarbonyl group, 1-acetimidoyl-4-piperazinecarbonyl group Group, (4-pyridyl) amino group, methylcarbamoyl group, phenyl group, cyclohexyl group, 1-piperazinesulfonyl group, 1-acetimidoyl-4-piperazinesulfonyl group, 4- (pyridyl) methyl group, 4-piperidi Ridenmethyl group, 4-piperidylmethyl group, 1-acetate Imidoyl-4-piperidylidenemethyl group, 1-acetimidoyl-4-piperidylmethyl group, 2-imidazolyl group, 1-phenoxycarbonyl-4-piperidyloxy group, monoethoxyhydroxyphosphoryl group, diethoxyphosphoryl group, chlorine A benzamidine derivative or a pharmaceutically acceptable derivative thereof, which is an atom, 1- (aminoacetyl) -4-piperidyloxy group, trifluoromethyl group, benzylsulfonylamino group, guanidino group, phosphono group or aminoethyloxy group. Preferred salts are.
Here, in the general formula (1), a benzamidine derivative or a pharmaceutically acceptable salt thereof in which W is any one of a hydrogen atom, a methyl group, and a benzyl group is preferable.
Here, in the general formula (1), when X has a substituent, the substituent is a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an ethanesulfonyloxy group, a butanesulfonyloxy group, a 4-piperidyloxy group, 1 -Acetoimidoyl-4-piperidyloxy group, 1-benzyloxycarbonyl-4-piperidyloxy group, 4-piperidylmethyl group, (1-acetimidoyl-4-piperidyl) methyl group, 1-acetimidoyl-3 A benzamidine derivative or a pharmaceutically acceptable salt thereof which is any one of -pyrrolidyloxy group, isopropyl group, 3-indolyl group and iodine atom is preferable.
Here, in the general formula (1), benzamidine, wherein Z is any one of a hydrogen atom, an iodine atom, a methyl group, a 2-carboxyl-2-oxoethyl group or a 2- (2-furyl) -2-oxoethyl group Derivatives or pharmaceutically acceptable salts thereof are preferred.
Or in general formula (1), L shows the organic group of Formula (2), and in Formula (2), W is a hydrogen atom, a C1-C6 alkyl group, and a C4-C10 aryl group. Or an aralkyl group having 5 to 12 carbon atoms,
X represents a hydrogen atom, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a methyl, ethyl or benzyl group which may have a substituent, and the substituent in the case of having a substituent includes a carboxyl group, carbon An alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, an alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, and a carbon number 6-8 piperidylalkyl groups, C8-11 iminoalkylpiperidylalkyl groups, C9-15 alkoxycarbonylpiperidylalkyl groups, pyrrolidyloxy groups, C6-9 iminoalkylpyrrolidyloxy groups, C7-13 alkoxycarbonylpyrrolidyloxy It represents a group,
V is a hydrogen atom, a substituted benzoyl group, an optionally substituted benzenesulfonyl, 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclide. A diunimilacetyl or an optionally substituted alkanesulfonyl group having 1 to 6 carbon atoms;
Examples of the substituent when V has a substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an aminoalkyl group having 1 to 3 carbon atoms, an alkylaminoalkyl group having 2 to 7 carbon atoms, and 4 carbon atoms. C-10 N-alkyl-N-alkoxycarbonylaminoalkyl group, piperidyloxy group, C7-10 iminoalkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, carbon number 6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C3-7 hydroxycarbonylalkyl group, C4-8 alkoxycarbonylalkyl group, 3-3 carbon atoms 7 hydroxycarbonylalkenyl group, alkoxycarbonylalkoxy having 4 to 8 carbon atoms Include group,
Or V shows the organic group of Formula (6), (in Formula (6), R 1 Represents a hydrogen atom, an alkoxycarbonyl group or a methyl group, and R 2 Represents a methyl group, a butyl group, a benzyl group, an aminobutyl group, a hydroxycarbonylethyl group, a hydroxycarbonylpropyl group or an imidazolylmethyl group; Three Represents a hydrogen atom. ),
Y represents any one of the formulas (7), (8), (9), (10) or (11), and in the formula (7), n is 1 or 2, and in the formula (8), n is 1 and
Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group or formula (12-1), and in formula (12-1), R Four Is preferably a benzamidine derivative or a pharmaceutically acceptable salt thereof, which represents either a carboxyl group or an aryl group having 4 to 10 carbon atoms.
Here, in the general formula (1), when V has a substituent, the substituent is carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, aminocarbonyl group, amidino group, acetyl group, bromine atom, amino group, methylamino Group, t-butoxycarbonylamino group, aminomethyl group, (methylamino) methyl group, (Nt-butoxycarbonyl-N-methylamino) methyl group, 4-piperidyloxy group, 1-acetimidoyl-4- A benzamidine derivative which is any one of a piperidyloxy group, a 3-pyrrolidyloxy group, a 1-t-butoxycarbonyl-3-pyrrolidyloxy group, a 2-carboxylethenyl group, and a 2- (ethoxycarbonyl) ethenyl group, or a derivative thereof Pharmaceutically acceptable salts are preferred.
Here, in the general formula (1), a benzamidine derivative or a pharmaceutically acceptable salt thereof in which W is any one of a hydrogen atom, a methyl group, and a benzyl group is preferable.
Here, in the general formula (1), when X has a substituent, the substituent is a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an ethanesulfonyloxy group, a butanesulfonyloxy group, a 4-piperidyloxy group, 1- Acetimidoyl-4-piperidyloxy group, 1-benzyloxycarbonyl-4-piperidyloxy group, 4-piperidylmethyl group, (1-acetimidoyl-4-piperidyl) methyl group, 1-acetimidoyl-3- A benzamidine derivative or a pharmaceutically acceptable salt thereof which is any pyrrolidyloxy group is preferred.
Here, in General Formula (1), Z is a hydrogen atom, an iodine atom, a methyl group, a 2-carboxyl-2-oxoethyl group, or a 2- (2-furyl) -2-oxoethyl group, or a benzamidine derivative or Its pharmaceutically acceptable salt is preferred.
Or, in general formula (1), L represents an organic group of formula (2) or formula (4), and in formula (2), W represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
X represents a hydrogen atom, a carboxyalkyl group having 2 to 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, and a mono or dialkylcarbamoyl group having 2 to 7 carbon atoms. Group, amidino group, mono- or dialkylamidino group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, halogeno group, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, 4 to 6 carbon atoms Arylamino group, alkoxycarbonylamino group having 2 to 7 carbon atoms, aminoalkyl group having 1 to 3 carbon atoms, mono- or dialkylaminoalkyl group having 2 to 7 carbon atoms, N-alkyl-N- having 4 to 10 carbon atoms Alkoxycarbonylaminoalkyl group, piperidyloxy group, C7-10 iminoalkylpi Lysyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, C6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C2-2 7 hydroxycarbonylalkyl group, C3-C8 alkoxycarbonylalkyl group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, C4-C10 aryl group, carbon C6-C12 arylalkenyl group, C1-C10 alkoxy group, nitro group, trifluoromethyl group, C3-C8 alkyl group, C4-C10 arylsulfonyl group, C5-C12 Arylalkyl group, piperazine carbonyl group, iminoalkyl having 7 to 10 carbon atoms Piperazine carbonyl group, piperazine sulfonyl group, iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, benzylsulfonylamino group, piperidylalkyl group having 6 to 9 carbon atoms, iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms, carbon number 6 -9 piperididenealkyl group, 8-12 carbon iminoalkylpiperidenealkyl group, guanidino group, phosphono group, 2-9 carbon dialkoxyphosphoryl group, 1-4 carbon monoalkoxyhydroxyphosphoryl Groups, aminoethyloxy groups, C 3-6 dialkylaminosulfonyl groups, C 2-4 dialkylguanidino groups,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
Z represents a hydrogen atom, (12-2-1), or (12-3),
Figure 0004103147
(R 51 Is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 6 Is either a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 7 carbon atoms, R 7 Represents either a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ]]
A benzamidine derivative or a pharmaceutically acceptable salt thereof is preferred.
Here, in the general formula (1), a benzamidine derivative or a pharmaceutically acceptable salt thereof, in which L represents an organic group of the formula (2), is preferable.
Here, in General formula (1), L shows the organic group of Formula (2), In Formula (2), W shows a hydrogen atom or a C1-C6 alkyl group,
X represents a hydrogen atom, a carboxyalkyl group having 2 to 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent, and examples of the substituent include a carbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an amidino group, a mono- or 2 to 7 carbon atoms Dialkylamidino group, acyl group having 2 to 8 carbon atoms, dialkylamino group having 2 to 6 carbon atoms, arylamino group having 4 to 6 carbon atoms, dialkylaminoalkyl group having 3 to 7 carbon atoms, piperidyloxy group, carbon number 7-10 iminoalkylpiperidyloxy group, pyrrolidyloxy group, C6-C9 iminoalkylpyrrolidyloxy group, C4-C10 aryl group, C6-C12 arylalkenyl group, C6-C6 -10 alkoxy group, C3-C8 alkyl group, C4-C10 arylsulfonyl group, charcoal C7-9 iminoalkylpiperazinecarbonyl group, C6-9 iminoalkylpiperazinesulfonyl group, C6-9 piperidylalkyl group, C8-12 iminoalkylpiperidylalkyl group, C6-9 A benzamidine derivative or a pharmaceutically acceptable salt thereof, such as a piperididenealkyl group, an iminoalkylpiperididenealkyl group having 8 to 12 carbon atoms, or a guanidino group, is preferable.
Here, in the general formula (1), L represents an organic group of the formula (2), in the formula (2), W represents a hydrogen atom or a methyl group, X represents a hydrogen atom, and 2 to 3 carbon atoms. A carboxyalkyl group or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a 1- (pyridyl) -piperidine-4-carbonyl group or a benzoyl group having a substituent, and the substituent includes a dialkylcarbamoyl group having 3 to 7 carbon atoms, a dialkylamidino group having 3 to 7 carbon atoms, Benzoyl group, dialkylamino group having 2 to 6 carbon atoms, pyridylamino group, iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, iminoalkylpyrrolidyloxy group having 6 to 9 carbon atoms, pyridylalkyl group having 6 to 7 carbon atoms , An iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms, an iminoalkylpiperidenealkyl group having 8 to 12 carbon atoms, and a guanidino group,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
A benzamidine derivative or a pharmaceutically acceptable salt thereof in which Z is a hydrogen atom, and represents the formula (12-2-1) is preferable.
Here, in general formula (1), L represents an organic group of formula (2), W in formula (2) represents a hydrogen atom, X represents a hydrogen atom, a C2-C3 carboxylalkyl. A group or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a 1- (4-pyridyl) -piperidine-4-carbonyl group or a benzoyl group having a substituent at the para position, and the substituent includes a dimethylcarbamoyl group, a (pyrrolidin-1-yl) carbonyl group, N , N-dimethylamidino group, (pyrrolidin-1-yl) (imino) methyl group, benzoyl group, 1-pyrrolidyl group, 4-pyridylamino group, 1-acetimidoyl-4-piperidyloxy group, 4-pyridylethyl group , A guanidino group,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
A benzamidine derivative or a pharmaceutically acceptable salt thereof, wherein Z represents the formula (12-2-1) is preferable.
Or, in general formula (1), L represents an organic group of formula (2), in formula (2), W represents a hydrogen atom,
X represents a carboxyalkyl group having 2 to 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent at the meta position or para position, and the substituent includes a mono- or dialkylamidino group having 2 to 7 carbon atoms, a pyridyl group, a carboxyl group, an amidino group. A dialkylaminocarbonyl group having 3 to 6 carbon atoms, a dialkylaminosulfonyl group having 3 to 6 carbon atoms, an imidazolin-2-yl-amino group, a pyrrolidyl group, a piperidyloxy group, and an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms. Are mentioned,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
Z represents either (12-2-1) or (12-3),
A benzamidine derivative or a pharmaceutically acceptable salt thereof is preferred.
Here, in the general formula (1), Z is a 2-acetamido-2-ethoxycarbonylethenyl group, a 2-acetamido-2-methoxycarbonylethenyl group, a 2-acetamido-2-carboxylethenyl group, or 2- A benzamidine derivative or a pharmaceutically acceptable salt thereof which is any of carboxy-2-oxoethyl groups is preferred.
Here, in the general formula (1), a benzamidine derivative or a pharmaceutically acceptable salt thereof in which X is either an ethoxycarbonylmethyl group or a carboxymethyl group is preferable.
Here, in the general formula (1), V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent at the para position, and examples of the substituent include an amidino group, a carboxyl group, a dimethylaminocarbonyl group, 1- A benzamidine derivative or a pharmaceutically acceptable salt thereof which is any of a pyrrolidylcarbonyl group, 4-piperidyloxy group or 1-acetimidoyl-4-piperidyloxy group is preferable.
Or, in general formula (1), L represents an organic group of formula (2),
W represents a hydrogen atom,
X represents a benzyl group having a substituent, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, and 7 to 10 carbon atoms. Iminoalkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, C6-8 piperidylalkyl group, C8-11 iminoalkylpiperidylalkyl group, C9-15 alkoxycarbonylpiperidyl group Alkyl group, pyrrolidyloxy group, iminoalkylpyrrolidyloxy group having 6 to 9 carbon atoms, alkoxycarbonylpyrrolidyloxy group having 7 to 13 carbon atoms, amidino group, benzyloxycarbonyl group, hydroxy group, halogeno group, amidinopiperidyl Oxy group or C1-C3 alkyl Group, and the like,
V is a hydrogen atom, 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinylamylacetyl, indolecarbonyl, phenylthiocarbonyl, pyridinecarbonyl, piperidinecarbonyl group or A benzimidoyl group or an optionally substituted alkanesulfonyl or benzenesulfonyl group having 1 to 6 carbon atoms is shown, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and 2 to 7 carbon atoms. Hydroxycarbonylalkyl group, C3-C8 alkoxycarbonylalkyl group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, phosphono group, C2-C9 Alkoxy phosphoryl groups include monoalkoxy hydroxy phosphoryl group having 1 to 4 carbon atoms,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
A benzamidine derivative or a pharmaceutically acceptable salt thereof, wherein Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, or any one of formulas (12-1), (12-2), and (12-3). Preferred salts are.
Here, X represents a benzyl group having a substituent, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, and a carbon number. 7-10 iminoalkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, C6-8 piperidylalkyl group, C8-11 iminoalkylpiperidylalkyl group, C9-15 carbon atom An alkoxycarbonylpiperidylalkyl group, a pyrrolidyloxy group, an iminoalkylpyrrolidyloxy group having 6 to 9 carbon atoms, and an alkoxycarbonylpyrrolidyloxy group having 7 to 13 carbon atoms,
V represents a hydrogen atom, benzenesulfonyl, 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinyl acetyl, or an alkanesulfonyl group having 1 to 6 carbon atoms. ,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
A benzamidine derivative or a pharmaceutically acceptable salt thereof, wherein Z represents either a hydrogen atom or formula (12-1) is preferred.
More specifically, although not limited to these, the compounds described in the examples are preferred.
In particular, (3R) -3- (4-amidinobenzoylamino) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] butanoic acid, (3R) -4- [5-amidino- 2- (2-carboxy-2-oxoethyl) phenoxy] -3- (4-dimethylcarbamoylbenzoylamino) butanoic acid, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy ] -3- (4-carboxylbenzoylamino) butanoic acid, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-carbonyl) ) Benzoylamino] butanoic acid, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (1- ( -Iminoethyl) piperidyl-4-oxy) benzoylamino] butanoic acid or (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1- A benzamidine derivative selected from the group consisting of (sulfonyl) benzoylamino] butanoic acid or a pharmaceutically acceptable salt thereof is preferred.
The compounds of Example 79, Example 213, and Example 206 are preferred. In addition, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-carbonyl) benzoylamino] of Example 193 and Example 191 Also preferred are butanoic acid, the compounds of Example 215, Example 205 and Example 7.
The amidino group in the compound of the general formula (1) may be protected by a suitable protecting group.
In the present invention, alkyl may contain a branch or a ring. For example, the alkyl group includes a cyclohexylmethyl group. Aryl represents not only an aromatic hydrocarbon ring group but also a heteroaromatic ring group having 1 to 3 heteroatoms selected from O, N and S. Specific examples of the aryl group include phenyl, pyridyl, imidazolyl, and pyrrolyl groups. For example, the arylalkenyl group includes 2- (4-pyridyl) vinyl group and the like. The dialkylamidino group refers to an N, N-dialkylamidino group and an N, N′-dialkylamidino group. In the dialkylcarbamoyl group, dialkylamidino group, dialkylamino group, dialkylaminoalkyl group, dialkylaminosulfonyl group and dialkylguanidino group, the two alkyl groups may be combined to form a ring. At this time, CH 2 May be substituted with O, NH, S, and CH 2 -CH 2 May be substituted with CH═CH. For example, a pyrrolidin-1-carbonyl group or the like is used for a dialkylcarbamoyl group, a 2-imidazolin-2-yl group, a (pyrrolidin-1-yl) (imino) methyl group or the like is used for a dialkylamidino group, and an imidazoline is used for a dialkylguanidino group. -2-amino group and the like are included. Acyl includes arylcarbonyl as well as alkylcarbonyl. For example, a benzoyl group etc. are contained in a C1-C8 acyl group. Alkoxy represents not only alkyloxy but also aryloxy and aralkyloxy. For example, an alkoxy group includes a cyclohexyloxy group, a phenoxy group, and the like, and an alkoxycarbonyl group includes a benzyloxycarbonyl group and the like.
In the present invention, aryl means not only an aromatic hydrocarbon ring group but also an aromatic heterocyclic group. For example, specific examples of the arylalkenyl group include 2- (4-pyridyl) vinyl group. The di-alkylamidino group represents an N, N-dialkylamidino group and an N, N′-dialkylamidino group. In the di-alkylcarbamoyl group, di-alkylamidino group, di-alkylamino group, and di-alkylaminoalkyl group, two alkyl groups may be bonded to form a ring. For example, specific examples of the di-alkylcarbamoyl group include 1-pyrrolidinecarbonyl group, and specific examples of the di-alkylamidino group include 2-imidazolin-2-yl group. Alkoxy represents not only alkyloxy but also aryloxy. For example, specific examples of the alkoxycarbonylpiperidyloxy group include a 1-phenoxycarbonyl-4-piperidyloxy group.
The compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers and optical isomers, and isolated compounds. .
Hereinafter, representative production methods of the compound (1) of the present invention will be described.
(Production method in the case where L represents the formula (2))
For example, dimethylformamide or the like is used as a solvent, for example, dimethylformamide protected on the nitrogen with, for example, a benzyloxycarbonyl group or a t-butoxycarbonyl group, and 3-cyanophenol is allowed to act in the presence of a base such as potassium carbonate. By this, the benzonitrile derivative (14) can be obtained. And the protecting group on nitrogen of the obtained benzonitrile derivative (14) can obtain an amine (15) by deprotecting in acidic solutions, such as a dioxane solution of 4N hydrogen chloride, for example.
Figure 0004103147
Subsequently, in the general formula (1), V is a benzoyl group having a substituent, or an optionally substituted cinnamoyl group, piperidinecarbonyl group, phenylacetyl group, or an organic group of the formula (6). In the case of being represented, amide (16) can be obtained by using, for example, dichloromethane or the like as a solvent and allowing amine (15) to react with an acylating agent in the presence of a base such as diisopropylethylamine.
In the general formula (1), when V is represented by an optionally substituted alkanesulfonyl group having 1 to 6 carbon atoms, a benzenesulfonyl group, or a naphthalenesulfonyl group, for example, dimethyl Amide (16) can be obtained by reacting amine (15) with a sulfonylating agent in the presence of a base such as triethylamine using formamide or the like.
Figure 0004103147
Here, in the general formula (1), when W is represented by an organic group other than hydrogen, dimethylformamide or the like is used as a solvent, and a base such as sodium hydride is allowed to act on the amide (16). Then, an amide (17) having W introduced on nitrogen can be obtained by acting an alkylating agent.
Figure 0004103147
The amide (17) thus obtained is converted to an amidino group by allowing an alcohol such as ethanol containing hydrogen halide such as hydrogen chloride to act and subsequently reacting with ammonia. Can do. By such a process, the benzamidine derivative (18) in which Y is represented by the above formula (7) and Z is represented by a hydrogen atom in the general formula (1) can be produced.
Figure 0004103147
When Z is represented by a 2-oxo-2-carboxyethyl group, 5-cyano-2-iodophenol is used as a starting material, and a 4-iodobenzonitrile derivative ( After obtaining 19), it can be led to an acrylic acid derivative (20) by condensing this with, for example, methyl 2-acetylaminoacrylate by a reaction such as Heck reaction. Then, in the same manner as above, the cyano group is converted to an amidino group, and the ester moiety on the 4-position substituent and the enamino moiety are simultaneously hydrolyzed, whereby Y in the general formula (1) is represented by the formula (7). And benzamidine derivative (21) in which Z is represented by a 2-oxo-2-carboxyethyl group can be produced.
Figure 0004103147
(Production method in the case where L represents the formula (3))
After obtaining a benzonitrile derivative (23) using 3-nitrophenylalkyl halide (22) in the same manner as in the production method of (14) above, an amine (24) is obtained by reacting, for example, zinc with acetic acid as a solvent. ) Can be obtained. Using this amine, acylation or sulfonylation was carried out in the same manner as in the production method of (16), and then the cyano group was converted to an amidino group in the same manner as above, whereby Y in the general formula (1) A benzamidine derivative represented by the formula (7) in which Z is a hydrogen atom can be obtained.
Figure 0004103147
(Production method in the case where L represents the formula (4))
When V is a benzoyl group having a substituent, for example, as shown in Example 63 below, an oxoalkyl halide (25) is prepared, and a benzonitrile derivative (26) is obtained in the same manner as in the production method of (14). It is done. At this time, the ketone of the oxoalkyl halide (25) may be reacted after being converted to, for example, acetal for protection. By converting the cyano group of the benzonitrile derivative (26) to an amidino group in the same manner as described above, a benzamidine derivative in which Y is represented by the above formula (7) and Z is a hydrogen atom in the general formula (1) is obtained. Can do.
Figure 0004103147
(Production method when L represents the above formula (5))
For example, as shown in Example 67 below, a carboxylic acid (27) is prepared, and this is activated by, for example, the action of ethyl chloroformate in the presence of a base, and the amide (28) is obtained by the action of an appropriate amine. be able to. By converting a cyano group to an amidino group in the same manner as described above, a benzamidine derivative in which Y is represented by the above formula (7) and Z is a hydrogen atom in the general formula (1) can be obtained.
Figure 0004103147
The benzamidine derivative of the present invention can also be produced by the following steps.
That is, aminoalkyl alcohol (29) protected with, for example, a benzyloxycarbonyl group or t-butoxycarbonyl group and 3-cyano-5-iodophenol on nitrogen, for example, THF or the like as a solvent, for example, triphenylphosphine or the like The benzonitrile derivative (30) can be obtained by reacting an azodicarbonyl compound such as diethyl azodicarboxylate in the presence. Then, the amine (31) can be obtained by deprotecting the protecting group on nitrogen of the obtained benzonitrile derivative (30) in an acidic solution such as a dioxane solution of 4N hydrogen chloride.
Figure 0004103147
(In the formula, X represents a carboxyalkyl group having 2 to 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms.)
Subsequently, using, for example, dichloromethane or the like as a solvent, a condensation agent is allowed to act on the amine (31) in the presence of a base such as triethylamine, thereby performing condensation with the carboxylic acid (32) to obtain the amide (33). be able to.
Figure 0004103147
(In the formula, A represents a substituent.)
The amide (33) thus obtained is condensed with an acrylic acid derivative such as methyl 2-acetamidoacrylate, for example, by a reaction such as Heck reaction, using acetonitrile or the like as a solvent, to the acrylic acid derivative (34). Can lead.
Figure 0004103147
The acrylic acid derivative (34) is reacted with an alcohol such as ethanol containing hydrogen halide such as hydrogen chloride, and then reacted with an ammonium salt such as ammonium carbonate to thereby convert the cyano group into an amidino group. Can be converted to By such a process, the benzamidine derivative (35) in which Z is represented by the above formula (12-3) in the general formula (1) can be produced.
Figure 0004103147
When Z is represented by a 2-carboxy-2-oxoethyl group, the benzamidine derivative (35) is hydrolyzed with an ester moiety and an enamino moiety on the 4-position substituent in an aqueous solution of hydrogen halide such as hydrogen chloride. The benzamidine derivative (36) in which Z is represented by a 2-carboxy-2-oxoethyl group in the general formula (1) can be produced by simultaneously performing the steps.
Figure 0004103147
The compound represented by the general formula (1) and the salt thereof thus produced are known separation and purification means such as extraction, concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, transfer dissolution, various chromatographies. It can be isolated and purified by chromatography or the like.
The salt of the benzamidine derivative represented by the general formula (1) may be any pharmaceutically acceptable salt, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, lactic acid, Examples include acid addition salts with organic acids such as salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, tosylic acid, methanesulfonic acid, and benzenesulfonic acid.
The compound represented by the general formula (1) or a salt thereof is administered as it is or as various pharmaceutical compositions. The dosage form of such a pharmaceutical composition may be, for example, a tablet, powder, pill, granule, capsule, suppository, solution, dragee, or devoted drug, using ordinary formulation aids. Can be manufactured according to conventional methods. For example, tablets may contain benzamidine derivatives, which are active ingredients of the present invention, known auxiliary substances such as lactose, inert diluents such as calcium carbonate or calcium phosphate, binders such as gum arabic, corn starch or gelatin, alginic acid, corn starch or the like It is obtained by mixing with a swelling agent such as gelatinized starch, a sweetener such as sucrose, lactose or saccharin, a flavoring agent such as peppermint, red mono oil or cherry, and a lubricant such as magnesium stearate, talc or carboxymethylcellulose. .
When the benzamidine derivative represented by the general formula (1) is used as an anticoagulant, the administration route may be either oral or parenteral, and the dosage depends on the patient's age, weight, condition, and administration method. Although it is different, the daily dose to an adult is usually 0.01 to 1000 mg, preferably 0.1 to 50 mg in the case of oral administration, and 1 μg to 100 mg, preferably 0 in the case of parenteral administration. 0.01 to 10 mg.
Hereinafter, the present invention will be described in detail by way of examples. These are preferred embodiments of the present invention, and the present invention is not limited to these examples.
In addition, the NMR spectrum in DMSO-d6 of the compound in which Z is represented by a 2-carboxy-2-oxoethyl group in the formula (1) in this example was a mixture of a keto form and an enol form.
Example 1
N- [2- (3-Amidinophenoxy) ethyl] -4-amidinobenzthioamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of t-butyl (2-bromoethyl) carbamate
2-Bromoethylamine hydrobromide 9.22 g (45 mmol) was dissolved in 100 ml of dichloromethane, and 7.64 g (35 mmol) of di-t-butyl dicarbonate, 10.0 g (99 mmol) of triethylamine, 4- (dimethylamino) 100 mg (0.82 mmol) of pyridine was added and stirred overnight. The title compound was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent.
Yield 5.99 g (26.7 mmol) Yield 76%
H-NMR (CDCl3) δ1.45 (1H, s), 3.46 (2H, dt), 3.51 (2H, t), 4.95 (1H, br)
Process 2
Synthesis of 3- [2- (t-butoxycarbonylamino) ethoxy] benzonitrile
5.85 g (29 mmol) of t-butyl (2-bromoethyl) carbamate is dissolved in 100 ml of dimethylformamide, and 2.38 g (26.4 mmol) of 3-hydroxybenzonitrile, 3.04 g (53 mmol) of potassium carbonate, sodium iodide 4 .31 g (53 mmol) was added and stirred at 50 ° C. for 6 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 3.33 g (13.3 mmol) Yield 51%
H-NMR (CDCl3) δ1.44 (1H, s), 3.55 (2H, dt), 4.05 (2H, t), 4.95 (1H, brs), 7.12 (1H, d), 7.14 (1H, s), 7.26 (1H, d), 7.38 (1H, t)
Process 3
Synthesis of 3- (2-aminoethoxy) benzonitrile
1.41 g of 3- [2- (t-butoxycarbonylamino) ethoxy] benzonitrile was dissolved in 20 ml of 4N hydrogen chloride in dioxane and stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was suspended in dichloromethane and collected by filtration to give the hydrochloride of the title compound.
Yield 0.89 g (4.48 mmol) Yield 83%
Further, this hydrochloride was dissolved in 1N aqueous sodium hydroxide solution and treated according to a conventional method using ethyl acetate as an extraction solvent to obtain the title compound.
H-NMR (CDCl3) δ 3.10 (2H, t), 4.00 (2H, t), 7.15 (1H, d), 7.17 (1H, s), 7.25 (1H, d), 7.37 (1H, t)
Process 4
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide
1.13 g (7.68 mmol) of 4-cyanobenzoic acid and 1.6 ml (14.1 mmol) of N-methylmorpholine are dissolved in 30 ml of dimethylformamide, and 0.67 ml (7.05 mmol) of ethyl chloroformate is added under ice water cooling. It was. After stirring for 5 minutes, 1.27 g (6.41 mmol) of 3- (2-aminoethoxy) benzonitrile was added and stirred at room temperature for 1 hour. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 1.29 g (4.43 mmol) Yield 69%
MS (FAB, m / z) 292 (MH +)
H-NMR (CDCl3) δ 3.91 (2H, dt), 4.19 (2H, t), 6.78 (1H, br), 7.14 (1H, d), 7.17 (1H, s), 7.28 (1H, d), 7.39 (1H, t), 7.75 (2H, d), 7.90 (2H, d)
Process 5
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzthioamide
1.46 g (5.00 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide is dissolved in 50 ml of toluene and 2,4-bis (4-methoxyphenyl) -1,3-dithia is dissolved. -2,4-Diphosphetane-2,4-disulfide (3.03 g, 7.5 mmol) was added and heated to reflux for 4 hours. After removing the precipitate by filtration, the solvent was distilled off under reduced pressure. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.16 g (3.77 mmol) Yield 75%
H-NMR (CDCl3) δ 3.85 (2H, dt), 4.30 (2H, t), 7.15 (1H, d), 7.17 (1H, s), 7.24 (1H, d), 7.39 (1H, t), 7.65 (2H, d), 7.81 (2H, d), 8.02 (1H, br)
Step 6
N- [2- (3-Amidinophenoxy) ethyl] -4-amidinobenzthioamide Synthesis of ditrifluoroacetate
A solution of 1.16 g (3.77 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzthioamide in 18 ml of 4N hydrogen chloride in dioxane contains 30% hydrogen chloride (w / V) 2 ml of ethanol was added. After stirring at room temperature for 96 hours, the residue obtained by distilling off the solvent under reduced pressure was dissolved in 20 ml of an ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 24 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 909 mg (1.59 mmol) Yield 42%
MS (ESI, m / z) 342 (MH +)
H-NMR (DMSO-d6) δ4.12 (2H, dt), 4.41 (2H, t), 7.35 (1H, d), 7.40 (1H, d), 7.41 (1H, s), 7.55 (1H, t ), 7.82 (2H, d), 7.88 (2H, d), 9.20 (2H, br), 9.30 (4H, br), 9.39 (2H, br), 9.47 (1H, t)
Example 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-carbamoylbenzamide trifluoroacetate
Process 1
Synthesis of benzyl-N- (2-bromoethyl) carbamate
2-Bromoethylamine hydrobromide 10 g (49 mmol) and triethylamine 15 ml were dissolved in dichloromethane, benzyl chloroformate 7.8 ml (49 mmol) was added under ice-cooling, and the mixture was stirred at room temperature. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 10.6 g (41 mmol) Yield 84%
H-NMR (CDCl3) δ3.45 (2H, t), 3.60 (2H, dt), 5.10 (2H, s), 5.20 (1H, brs), 7.30-7.38 (5H, m)
Process 2
Synthesis of 3- (2-aminoethoxy) benzonitrile hydrobromide
8 g of benzyl-N- (2-bromoethyl) carbamate, 3.7 g of 3-hydroxybenzonitrile, 4.3 g of calcium carbonate, 5.1 g of potassium iodide and 1.1 g of tetrabutylammonium iodide were stirred in dimethylformamide at 60 ° C. did. After treating with ethyl acetate as an extraction solvent according to a conventional method, purification by silica gel chromatography gave 3- [2- (benzyloxycarbonylamino) ethoxy] benzonitrile. To this was added acetic acid containing 20% hydrogen bromide under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off and the residue was washed with ethyl acetate to obtain the title compound.
Yield 4g
H-NMR (DMSO-d6) δ 3.25 (2H, m), 4.25 (2H, t), 7.35 (1H, d), 7.45 (1H, d), 7.50 (1H, s), 7.55 (1H, t ), 8.00 (3H, br)
Process 3
Synthesis of 4- [N- [2- (3-cyanophenoxy) ethyl] carbamoyl] benzoic acid methyl ester
1.50 g (6.2 mmol) of 3- (2-aminoethoxy) benzonitrile hydrobromide and 3 ml of triethylamine were stirred in 15 ml of dimethylformamide under ice-cooling, and 1.23 g (6. 2 mmol) was slowly added and stirred for 3 hours. After returning to room temperature, the reaction solution is diluted with 1N hydrochloric acid, extracted with ethyl acetate, the organic layer is washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is evaporated. To give the title compound.
Yield 1.4 g (4.3 mmol) Yield 70%
H-NMR (CDCl3) δ 3.90 (2H, dt), 3.93 (3H, s), 4.20 (2H, t), 6.60 (1H, br), 7.16 (1H, d), 7.17 (1H, s), 7.27 (1H, d), 7.39 (1H, t), 7.84 (2H, d), 8.12 (2H, d)
Process 4
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-carbamoylbenzamide
4- [N- [2- (3-Cyanophenoxy) ethyl] carbamoyl] benzoic acid methyl ester 100 mg (0.31 mmol) was stirred overnight in 100% 28% aqueous ammonia. The reaction mixture was evaporated under reduced pressure, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound.
Yield 98 mg (0.32 mmol) Yield 100%
H-NMR (DMSO-d6) δ3.62 (2H, dt), 4.20 (2H, t), 7.32 (1H, d), 7.40 (1H, d), 7.44-7.52 (3H, m), 7.88-7.96 (4H, m), 8.06 (1H, br), 8.80 (1H, t)
Process 5
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-carbamoylbenzamide trifluoroacetate
The title compound was obtained in the same manner as in Step 1 of Example 1 using 95 mg of N- [2- (3-cyanophenoxy) ethyl] -4-carbamoylbenzamide.
Yield 40.3 mg (0.09 mmol) Yield 30%
MS (ESI, m / z) 327 (MH +)
H-NMR (DMSO-d6) δ 3.70 (2H, dt), 4.20 (2H, t), 7.32-7.40 (3H, m), 7.48 (1H, br), 7.54 (1H, t), 7.89-7.97 (4H, m), 8.60 (1H, br), 8.84 (1H, brt), 9.06 (2H, brs), 9.28 (2H, brs)
Example 3
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N, N-dimethylcarbamoyl) benzamide trifluoroacetate
Process 1
Synthesis of 4- [N- [2- (3-cyanophenoxy) ethyl] carbamoyl] benzoic acid
3- [N- [2- (3-Cyanophenoxy) ethyl] carbamoyl] benzoic acid methyl ester (310 mg, 1 mmol) was stirred in ethanol (15 ml) and THF (15 ml), 1N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred overnight at room temperature. did. The reaction mixture was evaporated under reduced pressure, 1N hydrochloric acid was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound.
Yield 299 mg (0.96 mmol) Yield 96%
H-NMR (DMSO-d6) δ3.65 (2H, dt), 4.20 (2H, t), 7.32 (1H, d), 7.40 (1H, d), 7.44-7.52 (2H, m), 7.94 (2H , d), 8.02 (2H, d), 8.85 (1H, brt)
Process 2
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (N, N-dimethylcarbamoyl) benzamide
4- [N- [2- (3-Cyanophenoxy) ethyl] carbamoyl] benzoic acid 140 mg (0.45 mmol) was stirred in dimethylformamide, and triethylamine 50 mg (0.5 mmol) and ethyl chloroformate 48 mg (0 .45 mmol) was added and stirred for 5 minutes to make an acid anhydride, and then 1 ml (excess amount) of 50% dimethylamine aqueous solution was added. After returning to room temperature and stirring for 2 hours, the mixture was diluted with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. To give the title compound.
Yield 102 mg (0.30 mmol) Yield 67%
H-NMR (CDCl3) δ 2.90 (3H, br), 3.10 (3H, br), 3.90 (2H, dt), 4.20 (2H, t), 6.80 (1H, br), 7.16 (1H, d), 7.17 (1H, s), 7.26 (1H, d), 7.39 (1H, t), 7.45 (2H, d), 7.80 (2H, d)
Process 3
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N, N-dimethylcarbamoyl) benzamide trifluoroacetate
100 mg (0.32 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4- (N, N-dimethylcarbamoyl) benzamide was stirred in 5 ml of dioxane containing 4N hydrogen chloride, and 0.5 ml of ethanol was added. In addition, after stirring at room temperature for 2 days, the solvent was distilled off under reduced pressure. The obtained residue was stirred in 10 ml of ethanol, 80 mg of ammonium carbonate was added and stirred for 5 days at room temperature, the solvent was distilled off, and the resulting residue was reversed-phase high-speed using octadodecyl group chemically bonded silica gel as a filler. The title compound was obtained by liquid chromatography, eluting with a mixed solvent of water and acetonitrile containing 0.1% of trifluoroacetic acid (v / v), and lyophilizing the fraction of interest.
Yield 95 mg (0.2 mmol) Yield 63%
MS (ESI, m / z) 355 (MH +)
H-NMR (DMSO-d6) δ2.85 (3H, br), 3.00 (3H, br), 3.65 (2H, dt), 4.22 (2H, t), 7.31-7.41 (3H, m), 7.48 (2H , d), 7.54 (1H, t), 7.91 (2H, d), 8.80 (1H, t), 9.05 (2H, br), 9.30 (2H, br)
Example 4
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N-methyl-N-ethylcarbamoyl) benzamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (N-methyl-N-ethylcarbamoyl) benzamide
4- [N- [2- (3-cyanophenoxy) ethyl] carbamoyl] benzoic acid 258 mg (0.83 mmol), N-ethyl-N-methylamine 53 mg (0.9 mmol), 1-hydroxybenzotriazole (containing water, 87%) 129 mg (0.83 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 159 mg (0.83 mmol) were stirred in 10 ml dichloromethane overnight at room temperature. The mixture was diluted with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed successively with 1N aqueous sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound.
Yield 288 mg (0.82 mmol) Yield 99%
H-NMR (CDCl3) δ1.00-1.30 (3H, m), 2.82-3.62 (5H, m), 3.83 (2H, dt), 4.20 (2H, t), 7.12-7.41 (7H, m), 7.78 (2H, d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N-methyl-N-ethylcarbamoyl) benzamide trifluoroacetate
The title compound was obtained in the same manner as in Step 3 of Example 3 using 280 mg (0.8 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4- (N-methyl-N-ethylcarbamoyl) benzamide. .
Yield 242 mg (0.5 mmol) Yield 63%
MS (ESI, m / z) 369 (MH +)
H-NMR (DMSO-d6) δ1.00-1.20 (3H, brm), 2.80-3.00 (3H, br), 3.10-3.50 (2H, m), 3.70 (2H, dt), 4.20 (2H, t) , 7.34 (1H, d), 7.39 (1H, d), 7.40 (1H, s), 7.43-7.50 (2H, br), 7.54 (1H, t), 7.91 (2H, d), 8.80 (1H, br ), 9.10 (2H, br), 9.30 (2H, br)
Example 5
N- [2- (3-Amidinophenoxy) ethyl] -4- (2-imidazolin-2-yl) benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 4-ethoxycarbonimidoylbenzoic acid ethyl ester hydrochloride
4-Cyanobenzoic acid ethyl ester (5.16 g, 29 mmol) was stirred in 50 ml of dioxane containing 4N hydrogen chloride, 5 ml of ethanol was added thereto, and the mixture was stirred at room temperature for 4 days. The solvent was distilled off, and the residue was washed with ethyl acetate and dried to obtain the title compound.
Yield 3.24 g (12.6 mmol) Yield 43%
H-NMR (DMSO-d6) δ1.35 (3H, t), 1.50 (3H, t), 4.40 (2H, q), 4.65 (2H, q), 8.18 (2H, d), 8.25 (2H, d )
Process 2
Synthesis of 4- (2-imidazolin-2-yl) benzoic acid ethyl ester
4-Ethoxycarbonimidoylbenzoic acid ethyl ester 2.96 g (11.5 mmol) of hydrochloride and 690 mg (11.5 mmol) of ethylenediamine were stirred in 60 ml of ethanol at 60 ° C. for 4 hours. The solvent was distilled off, 1N aqueous sodium hydroxide was added, the mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound.
Yield 2.15 g (9.85 mmol) Yield 86%
H-NMR (CDCl3) δ1.40 (3H, t), 3.80 (4H, br), 4.40 (2H, q), 7.80 (2H, d), 8.02 (2H, d)
Process 3
Synthesis of 4- (2-imidazolin-2-yl) benzoic acid hydrochloride
1 g (4.58 mmol) of 4- (2-imidazolin-2-yl) benzoic acid ethyl ester was heated to reflux in 4 ml of hydrochloric acid and 8 ml of acetic acid, and the solvent was distilled off to obtain the title compound.
Yield 1.04 g (4.59 mmol) Yield 100%
H-NMR (DMSO-d6) δ 4.00 (4H, s), 8.20 (4H, s), 11.00 (2H, br)
Process 4
N- [2- (3-Amidinophenoxy) ethyl] -4- (2-imidazolin-2-yl) benzamide Synthesis of ditrifluoroacetate
4- (2-imidazolin-2-yl) benzoic acid hydrochloride 400 mg (1.76 mmol), 3- (2-aminoethoxy) benzonitrile hydrobromide 428 mg (1.76 mmol), 1-hydroxybenzotriazole ( Water content, 87%) 301 mg (1.94 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 372 mg (1.94 mmol), triethylamine 200 mg (2.00 mmol) in dimethylformamide at room temperature overnight. Stir. The solvent was distilled off under reduced pressure, subjected to reverse phase medium pressure liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and eluted with a mixed solvent of methanol and water. The fraction of the desired product was evaporated, and the residue was washed with ethyl acetate to obtain 400 mg of a condensate. Of this, 100 mg of the title compound was obtained in the same manner as in Example 3, Step 3.
Yield 117 mg (0.2 mmol)
MS (ESI, m / z) 352 (MH +)
H-NMR (DMSO-d6) δ3.70 (2H, dt), 4.00 (4H, s), 4.22 (2H, t), 7.30-7.42 (3H, m), 7.55 (1H, t), 8.02 (2H , d), 8.10 (2H, d), 9.05 (1H, t), 9.20-9.35 (4H, br), 10.7 (2H, s)
Example 6
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (1-piperidinecarbonyl) benzamide trifluoroacetate
Process 1
Synthesis of 4- (1-piperidinecarbonyl) benzoic acid
6 ml of piperidine was stirred in dichloromethane at 0 ° C., and 3 g (15 mmol) of terephthalic acid monomethyl ester chloride dissolved in dichloromethane was added. After returning to room temperature and stirring for 2 hours, the mixture was diluted with 1N hydrochloric acid and extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent was stirred in ethanol, 30 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off, the reaction mixture was concentrated, diluted with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated to remove the title compound. Obtained.
Yield 2.81 g (12 mmol) Yield 80%
H-NMR (CDCl3) δ1.45-1.75 (6H, br), 3.33 (2H, br), 3.75 (2H, br), 7.50 (2H, d), 8.15 (2H, d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (1-piperidinecarbonyl) benzamide trifluoroacetate
4- (1-piperidinecarbonyl) benzoic acid 300 mg (1.29 mmol), 3- (2-aminoethoxy) benzonitrile hydrochloride 255 mg (1.29 mmol), 1-hydroxybenzotriazole (hydrous, 87%) 200 mg (1 .29 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 247 mg (1.29 mmol), triethylamine 130.5 mg (1.29 mmol) and obtained in the same manner as in Step 4 of Example 4. The total amount of N- [2- (3-cyanophenoxy) ethyl] -4- (1-piperidinecarbonyl) benzamide was obtained in the same manner as in Step 3 of Example 3 to obtain the title compound.
Yield 370 mg (0.73 mmol) Yield 56%
MS (ESI, m / z) 395 (MH +)
H-NMR (DMSO-d6) δ 1.40-1.65 (6H, br), 3.25 (2H, br), 3.60 (2H, br), 3.65 (2H, dt), 4.25 (2H, t), 7.34 (1H , d), 7.39 (1H, d), 7.40 (1H, s), 7.45 (2H, d), 7.54 (1H, t), 7.91 (2H, d)
Example 7
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N, N-dimethylamidino) benzamide ditrifluoroacetate
Process 1
Synthesis of 4- (N, N-dimethylamidino) benzoic acid ethyl ester
4-Ethoxycarbonimidoyl benzoic acid ethyl ester hydrochloride 1 g (3.9 mmol) was stirred overnight in 3 ml of ethanol and 10 ml of 50% aqueous dimethylamine, and then the solvent was distilled off. 10 ml of dioxane containing 4N hydrogen chloride, After adding 1 ml of ethanol and stirring at room temperature for 5 days, the solvent was distilled off, 1N sodium hydroxide was added and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The title compound was obtained.
Yield 671 mg (3.05 mmol) Yield 78%
H-NMR (CDCl3) δ1.40 (3H, t), 2.95 (6H, s), 4.30 (1H, br), 4.40 (2H, q), 7.40 (2H, d), 8.10 (2H, d)
Process 2
N- [2- (3-Cyanophenoxy) ethyl] -4- (N, N-dimethylamidino) benzamide trifluoroacetate
670 mg (3.0 mmol) of 4- (N, N-dimethylamidino) benzoic acid ethyl ester was heated to reflux in 20 ml of 6N hydrochloric acid. The residue obtained by distilling off the solvent was added 10 ml of dichloromethane, 600 mg (3.0 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride, 575 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 3.0 mmol), 405 mg (3.0 mmol) of 1-hydroxybenzotriazole, and 303 mg (3.0 mmol) of triethylamine were added and stirred at room temperature for 5 days. 1N Aqueous sodium hydroxide solution was added and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent was filled with octadodecyl group chemically bonded silica gel. By subjecting to reverse phase high performance liquid chromatography, eluting with a mixed solvent of water and acetonitrile containing 0.1% of trifluoroacetic acid (v / v), and freeze-drying the fraction of interest. A compound was obtained.
Yield 716 mg (1.59 mmol) Yield 53%
H-NMR (DMSO-d6) δ2.98 (3H, s), 3.22 (3H, s), 3.65 (2H, dt), 4.22 (2H, t), 7.30-7.53 (4H, m), 7.70 (2H , d), 8.05 (2H, d), 8.92 (1H, br), 9.00 (1H, s), 9.40 (1H, s)
Process 3
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N, N-dimethylamidino) benzamide ditrifluoroacetate
N- [2- (3-Cyanophenoxy) ethyl] -4- (N, N-dimethylamidino) benzamide 506 mg (1.1 mmol) trifluoroacetate was used to give the title compound in the same manner as in Example 3, Step 3. Obtained.
Yield 389 mg (0.67 mmol) Yield 61%
MS (ESI, m / z) 354 (MH +)
H-NMR (DMSO-d6) δ 2.95 (3H, s), 3.22 (3H, s), 3.70 (2H, dt), 4.22 (2H, t), 7.34 (1H, d), 7.38-7.44 (2H , m), 7.54 (1H, t), 7.70 2H, d), 8.07 (2H, d), 9.00-9.42 (7H, m)
Example 8
N- [2- (3-Amidinophenoxy) ethyl] -4- (1,4,5,6-tetrahydro-pyrimidin-2-yl) benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (1,4,5,6-tetrahydro-pyrimidin-2-yl) benzamide trifluoroacetate
4-Ethoxybenzoic acid 10 g (68 mmol) was stirred in 100 ml of dioxane containing 4N hydrogen chloride and 10 ml of ethanol for 2 days, the solvent was distilled off, and the residue obtained was washed with ethyl acetate to give 4-ethoxy 500 mg out of 10.9 g of the mixture of carbonimidoylbenzoic acid and its ester, and 162 mg (2.18 mmol) of propylenediamine were stirred in 15 ml of ethanol at 60 ° C. for 2 hours. The solvent was distilled off, concentrated hydrochloric acid was added and the mixture was stirred at 60 ° C. for 5 hours. The solvent was distilled off, and the resulting residue was washed with ethyl acetate to give 4- (1,4,5,6-tetrahydro- Pyrimidin-2-yl) benzoic acid crude product (290 mg, 1.2 mmol) was obtained. 238 mg (1.2 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride, 230 mg (1.2 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole ( (Water content, 87%) 186 mg (1.2 mmol), triethylamine 122 mg (1.2 mmol), and dimethylformamide 10 ml were added and stirred at room temperature for 4 days. The solvent was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. It was subjected to reverse phase high performance liquid chromatography using dodecyl group chemically bonded silica gel as a packing material, and eluted with a mixed solvent of water and acetonitrile containing 0.1% trifluoroacetic acid (v / v). The fraction was lyophilized to give the title compound.
Yield 125mg
H-NMR (DMSO-d6) δ2.00 (2H, m), 3.50 (4H, br), 3.65 (2H, dt), 4.20 (2H, t), 7.32 (1H, d), 7.41 (1H, d ), 7.44-7.52 (2H, m), 7.81 (2H, d), 8.04 (2H, d), 8.94 (1H, t), 10.00 (2H, s)
Process 2
N- [2- (3-Amidinophenoxy) ethyl] -4- (1,4,5,6-tetrahydro-pyrimidin-2-yl) benzamide Synthesis of ditrifluoroacetate
Similar to Example 3, Step 3, using 117 mg (0.25 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4- (1,4,5,6-tetrahydro-pyrimidin-2-yl) benzamide. To give the title compound.
Yield 37 mg (0.06 mmol) Yield 24%
MS (ESI, m / z) 366 (MH +)
H-NMR (DMSO-d6) δ2.00 (2H, br), 3.50 (4H, br), 3.70 (2H, dt), 4.25 (2H, t), 7.30-7.45 (3H, m), 7.55 (1H , t), 7.82 (2H, d), 8.06 (2H, d), 9.03 (1H, br), 9.30 (2H, br), 9.40 (2H, br), 10.1 (2H, br)
Example 9
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (1-pyrrolidinecarbonyl) benzamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (1-pyrrolidinecarbonyl) benzamide
4- [N- [2- (3-Cyanophenoxy) ethyl] carbamoyl] benzoic acid 245 mg (0.79 mmol), pyrrolidine 62 mg (0.87 mmol), 1-hydroxybenzotriazole (hydrous, 87%) 123 mg (0. 79 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 151 mg (0.79 mmol), and the title compound was obtained in the same manner as in Step 1 of Example 4.
Yield 277 mg (0.76 mmol) Yield 96%
H-NMR (CDCl3) δ 1.80-2.00 (4H, m), 3.30-3.70 (4H, m), 3.85 (2H, dt), 4.20 (2H, t), 7.14-7.28 (4H, m), 7.38 (1H, t), 7.48 (2H, d), 7.79 (2H, d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (1-pyrrolidinecarbonyl) benzamide trifluoroacetate
The title compound was obtained in the same manner as in Step 3 of Example 3 using 270 mg (0.74 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4- (1-pyrrolidinecarbonyl) benzamide.
Yield 238 mg (0.48 mmol) Yield 65%
MS (ESI, m / z) 381 (MH +)
H-NMR (DMSO-d6) δ 1.75-1.90 (4H, m), 3.30-3.50 (4H, m), 3.70 (2H, dt), 4.20 (2H, t), 7.34 (1H, d), 7.39 (1H, d), 7.40 (1H, s), 7.54 (1H, t), 7.59 (2H, d), 7.91 (2H, d), 8.80 (1H, t), 9.10 (2H, br), 9.30 ( (2H, br)
Example 10
N- [2- (3-Amidinophenoxy) ethyl] -4-[(E) -2- (pyridin-4-yl) vinyl] benzamide Synthesis of ditrifluoroacetate
4- (diethoxyphosphorylmethyl) benzoic acid methyl 412 mg (1.44 mmol) was dissolved in tetrahydrofuran 50 ml. Under ice cooling, sodium hydride 63 mg (1.44 mmol) was added, stirred for 30 minutes and then returned to room temperature for 30 minutes. Stir. 154 mg (1.44 mmol) of pyridine-4-aldehyde was added and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and 5 ml of concentrated hydrochloric acid was added to the resulting residue, followed by stirring at 60 ° C. for 22 hours. The residue obtained by distilling off the solvent was dissolved in 10 ml of dichloromethane, 0.58 ml (4.17 mmol) of triethylamine, 176 mg (0.92 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1-hydroxybenzotriazole 124 mg (0.92 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 182 mg (0.83 mmol) were added and stirred for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue obtained was obtained in the same manner as in Example 1, step 6. Obtained.
Yield 150 mg (0.24 mmol) Yield 47%
MS (ESI, m / z) 387 (MH +)
H-NMR (DMSO-d6) δ3.70 (2H, dt), 4.26 (2H, t), 7.32-7.50 (3H, m), 7.54 (1H, dd), 7.66-7.84 (5H, m), 7.95 (2H, d), 8.64 (2H, d), 8.82-8.90 (1H, m), 9.18 (2H, br), 9.39 (2H, br)
Example 11
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (1H-pyrrol-1-yl) benzamide trifluoroacetate
210 mg (1.12 mmol) of 4- (1H-pyrrol-1-yl) benzoic acid was dissolved in 10 ml of dichloromethane, 0.47 ml (3.36 mmol) of triethylamine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 236 mg (1.24 mmol) of hydrochloride, 167 mg (1.24 mmol) of 1-hydroxybenzotriazole, and 222 mg (1.12 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride were added and stirred for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 243 mg (0.53 mmol) Yield 47%
MS (ESI, m / z) 349 (MH +)
H-NMR (DMSO-d6) δ3.69 (4H, q), 3.63 (2H, dt), 4.24 (2H, t), 6.31 (2H, dd), 7.30-7.44 (3H, m), 7.45-7.60 (3H, m), 7.69 (2H, d), 7.95 (2H, d), 8.77 (1H, br), 9.12 (2H, br), 9.28 (2H, br)
Example 12
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-cyclohexyloxybenzamide trifluoroacetate
Process 1
Synthesis of ethyl 4-cyclohexyloxybenzoate
822 mg (4.95 mmol) of ethyl 4-hydroxybenzoate was dissolved in 20 ml of tetrahydrofuran, 545 mg (5.45 mmol) of cyclohexanol, 1.56 g (5.94 mmol) of triphenylphosphine, 202 mg (1.50 mmol) of diethyl azodicarboxylate. ) And stirred for 22 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give the title compound.
Yield 640 mg (2.58 mmol) Yield 52%
H-NMR (CDCl3) δ 1.32-1.44 (3H, m), 1.37 (3H, t), 1.48-1.63 (3H, m), 1.74-1.87 (2H, m), 1.93-2.20 (2H, m) 4.28-4.40 (1H, m), 4.34 (2H, q), 6.90 (2H, d), 7.97 (2H, d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-cyclohexyloxybenzamide trifluoroacetate
To 237 mg (0.95 mmol) of ethyl 4-cyclohexyloxybenzoate, 3 ml of 1N sodium hydroxide and 10 ml of ethanol were added and stirred for 20 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was dissolved in 10 ml of dichloromethane, and 0.73 ml (5.25 mmol) of triethylamine, 1- (3-dimethylaminopropyl) -3 -200 mg (1.05 mmol) of ethyl carbodiimide hydrochloride, 141 mg (1.05 mmol) of 1-hydroxybenzotriazole, and 188 mg (0.95 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 162 mg (0.77 mmol) Yield 34%
MS (ESI, m / z) 382 (MH +)
H-NMR (DMSO-d6) δ 1.30-1.58 (6H, m), 1.64-1.75 (2H, m), 1.88-1.98 (2H, m), 3.67 (2H, dt), 4.20 (2H, t) , 4.37-4.48 (2H, m), 6.98 (2H, d), 7.33 (1H, d), 7.39 (2H, br), 7.53 (1H, dd), 7.81 (2H, d), 8.56 (1H, br ), 9.08 (2H, br), 9.26 (2H, br)
Example 13
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-diethylaminobenzamide trifluoroacetate
210 mg (1.09 mmol) of 4-diethylaminobenzoic acid was dissolved in 10 ml of dichloromethane, 0.76 ml (5.45 mmol) of triethylamine, 229 mg (1.20 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1-hydroxybenzotriazole 162 mg (1.20 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 215 mg (1.09 mmol) were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue obtained was obtained by subjecting the residue to the same procedure as in Example 1, step 6. Got.
Yield 410 mg (0.88 mmol) Yield 80%
MS (ESI, m / z) 355 (MH +)
H-NMR (DMSO-d6) δ 1.10 (6H, t), 3.38 (4H, q), 3.63 (2H, dt), 4.18 (2H, t), 6.66 (2H, d), 7.32-7.40 (3H , m), 7.53 (1H, dd), 7.71 (2H, d), 8.31 (1H, br), 9.04 (2H, br), 9.28 (2H, br)
Example 14
N- [2- (3-Amidinophenoxy) ethyl] -4- [2- (pyridin-4-yl) ethyl] benzamide Synthesis of ditrifluoroacetate
N- [2- (3-Amidinophenoxy) ethyl] -4-[(E) -2- (pyridin-4-yl) vinyl] benzamide 50 mg (0.08 mmol) of ditrifluoroacetate was dissolved in 5 ml of methanol. Then, 50 mg of palladium-carbon was added and stirred for 20 hours in the presence of hydrogen. After filtration through celite, the residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / V) The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 7 mg (0.01 mmol) Yield 14%
MS (ESI, m / z) 389 (MH +)
H-NMR (DMSO-d6) δ3.06 (2H, dt), 3.18 (2H, dt), 3.66 (2H, dt), 4.22 (2H, t), 7.29-7.45 (5H, m), 7.54 (1H , dd), 7.80 (4H, dd), 8.66-8.80 (3H, m), 9.30 (2H, br)
Example 15
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-nitrobenzamide trifluoroacetate
190 mg (1.14 mmol) of 4-nitrobenzoic acid was dissolved in 10 ml of dichloromethane, 0.47 ml (3.42 mmol) of triethylamine, 239 mg (1.25 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1-hydroxybenzotriazole 169 mg (1.25 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 225 mg (1.14 mmol) were added and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got. Yield 290 mg (0.66 mmol) Yield 58%
MS (ESI, m / z) 329 (MH +)
H-NMR (DMSO-d6) δ 3.71 (2H, dt), 4.25 (2H, t), 7.34 (1H, dd), 7.40 (2H, br), 7.54 (1H, t), 8.09 (2H, d ), 8.33 (2H, d), 9.10 (1H, br), 9.14 (2H, br), 9.28 (2H, br)
Example 16
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-trifluoromethylbenzamide trifluoroacetate
194 mg (1.02 mmol) of 4-trifluoromethylbenzoic acid was dissolved in 10 ml of dichloromethane, 0.43 ml (3.06 mmol) of triethylamine, 215 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1. 12 mmol), 152 mg (1.12 mmol) of 1-hydroxybenzotriazole, and 202 mg (1.02 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride were added and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 240 mg (0.56 mmol) Yield 51%
MS (ESI, m / z) 352 (MH +)
H-NMR (DMSO-d6) δ 3.69 (2H, dt), 4.24 (2H, t), 7.34 (1H, dd), 7.40 (2H, br), 7.54 (1H, dd), 7.86 (2H, d ), 8.06 (2H, d), 8.99 (1H, br), 9.12 (2H, br), 9.28 (2H, br)
Example 17
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-isopropylbenzamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-isopropylbenzamide
283 mg (1.73 mmol) of 4-isopropylbenzoic acid was dissolved in 10 ml of dichloromethane, 1.2 ml (8.65 mmol) of triethylamine, 363 mg (1.90 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1-hydroxybenzotriazole 256 mg (1.90 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 342 mg (1.24 mmol) were added and stirred for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the title compound. It was.
Yield 440 mg (1.43 mmol) Yield 83%
H-NMR (CDCl3) δ 2.96 (6H, s), 3.62 (2H, dt), 4.17 (2H, t), 6.70 (2H, d), 7.32-7.43 (3H, m), 7.54 (1H, t ), 7.74 (2H, d), 8.36 (1H, t), 9.05 (2H, br), 9.28 (2H, br)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-isopropylbenzamide trifluoroacetate
The title compound was obtained in the same manner as in Step 1 of Example 1 using 440 mg (1.43 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-isopropylbenzamide as a starting material.
Yield 170 mg (0.39 mmol) Yield 27%
MS (ESI, m / z) 326 (MH +)
H-NMR (DMSO-d6) δ1.20 (3H, s), 1.22 (3H, s), 2.83 + 3.03 (1H, m), 3.66 (2H, dt), 4.21 (2H, t), 7.33 (2H , d), 7.36-7.42 (2H, m), 7.53 (1H, dd), 7.79 (2H, d), 8.65 (1H, br), 9.16 (2H, br), 9.28 (2H, br)
Example 18
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (pyrrolidin-1-yl) benzamide trifluoroacetate
Process 1
Synthesis of ethyl 4- (pyrrolidin-1-yl) benzoate
1.69 g (10.2 mmol) of ethyl 4-aminobenzoate was dissolved in 10 ml of benzene, and 2.18 g (10.1 mmol) of 1,4-dibromobutane and 3.53 ml (20.2 mmol) of diisopropylethylamine were added. Heated to reflux for hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude title compound.
Yield 1.0 g (4.56 mmol) Yield 46%
H-NMR (CDCl3) δ1.37 (3H, t), 1.92-2.18 (4H, m), 3.21-3.47 (3H, m), 4.31 (2H, q), 6.50 (2H, d), 7.91 (2H , d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (pyrrolidin-1-yl) benzamide trifluoroacetate
To 343 mg (1.56 mmol) of ethyl 4- (pyrrolidin-1-yl) benzoate was added 5 ml of concentrated hydrochloric acid, and the mixture was stirred at 60 ° C. for 20 hours. The residue obtained by distilling off the solvent was dissolved in 10 ml of dichloromethane, 1.09 ml (7.80 mmol) of triethylamine, 329 mg (1.72 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1-hydroxybenzotriazole (233 mg, 1.72 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride (308 mg, 1.56 mmol) were added, and the mixture was stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was obtained according to the same procedure as in Example 1, step 6. A compound was obtained.
Yield 220 mg (0.43 mmol) Yield 30%
MS (ESI, m / z) 352 (MH +)
H-NMR (DMSO-d6) δ 1.96 (4H, t), 3.27 (4H, t), 3.62 (2H, dt), 4.20 (2H, t), 6.52 (2H, d), 7.38-7.39 (3H , m), 7.53 (1H, dd), 7.74 (2H, d), 8.38 (1H, br), 9.29 (2H, br), 9.37 (2H, br)
Example 19
Synthesis of 1-benzoyl-N- [2- (3-amidinophenoxy) ethyl] piperidine-4-carboxamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide 2.54 g (11.1 mmol) of (t-butoxycarbonyl) piperidine-4-carboxylic acid, 3- (2-aminoethoxy) Benzonitrile 2.00 g (10.1 mmol), triethylamine 1.4 ml (10.1 mmol), 1-hydroxybenzotriazole 1.50 g (11.1 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 2.13 g (11.1 mmol) of the salt was stirred overnight at room temperature in 15 ml of dimethylformamide. Ethyl acetate was used as an extraction solvent, and the mixture was treated according to a conventional method to obtain 1- (t-butoxycarbonyl) -N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide crude product. This crude product was stirred at room temperature for 4 hours in a mixed solution of 5 ml (20.1 mmol) of dioxane containing 4N hydrogen chloride and 10 ml of dioxane. The solvent was distilled off, 1N aqueous sodium hydroxide solution was added, and the mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain the title compound.
Yield 1.73 g (6.34 mmol) Yield 63%
MS (ESI, m / z) 274 (MH +)
H-NMR (CDCl3) δ 1.64 (2H, ddd), 1.84 (2H, d), 2.14 (2H, s), 2.28 (1H, tt), 2.64 (2H, ddd), 3.16 (2H, dt), 3.70 (2H, t), 4.06 (2H, t), 6.00 (1H, brs), 7.14 (1H, d), 7.15 (1H, s), 7.26 (1H, d), 7.38 (1H, t)
Process 2
Synthesis of 1-benzoyl-N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide
175 mg (1.43 mmol) of benzoic acid, 430 mg (1.58 mmol) of N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide, 0.22 ml (1.58 mmol) of triethylamine, 1-hydroxybenzotriazole 213 mg (1.58 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 303 mg (1.58 mmol) were stirred overnight at room temperature in 10 ml of dimethylformamide. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 458 mg (1.21 mmol) Yield 85%
MS (ESI, m / z) 378 (MH +)
H-NMR (CDCl3) δ 1.60-2.00 (5H, m), 2.38-2.40 (2H, m), 2.80-3.01 (2H, m), 3.62 (2H, t), 4.02 (2H, t), 6.40 (1H, brs), 7.15 (2H, brs), 7.25 (1H, d), 7.32-7.40 (6H, m)
Process 3
Synthesis of 1-benzoyl-N- [2- (3-amidinophenoxy) ethyl] piperidine-4-carboxamide trifluoroacetate
458 mg (1.21 mmol) of 1-benzoyl-N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide is stirred in 10 ml of dioxane containing 4N hydrogen chloride, which contains 30% hydrogen chloride. (W / v) Ethanol (3.5 ml) was added, and the mixture was stirred at room temperature for 3 days. The obtained residue was dissolved in 15 ml of ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 2 days. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 514 mg (1.01 mmol) Yield 84%
MS (ESI, m / z) 395 (MH +)
H-NMR (DMSO-d6) δ1.52 (2H, t), 1.60-1.80 (2H, m), 2.38-2.42 (1H, m), 2.80-3.10 (2H, m), 3.45 (2H, t) , 3.50-3.64 (1H, m), 4.08 (2H, t), 4.20-4.50 (1H, m), 7.28 (1H, d), 7.30-7.48 (5H, m), 7.30-7.48 (5H, m) , 7.51 (1H, t), 8.12 (1H, t), 9.22 (4H, d)
Example 20
Synthesis of 1-benzenesulfonyl-N- [2- (3-amidinophenoxy) ethyl] piperidine-4-carboxamide trifluoroacetate
Process 1
Synthesis of 1-benzenesulfonyl-N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide
430 mg (1.58 mmol) of N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxyamide was dissolved in 10 ml of dimethylformamide, 0.2 ml (1.43 mmol) of triethylamine, 253 mg of benzenesulfonyl chloride (1. 43 mmol) was added at 0 ° C. and stirred for 13 hours. The title compound was obtained by treating in accordance with a conventional method using ethyl acetate as an extraction solvent. Yield 568 mg (1.37 mmol) Yield 96%
MS (ESI, m / z) 414 (MH +)
H-NMR (CDCl3) δ 1.80 (2H, dd), 1.90 (2H, td), 2.05 (1H, d), 2.40 (2H, td), 3.62 (2H, t), 3.76 (2H, dt), 4.05 (2H, t), 6.00 (1H, brs), 7.10 (2H, t), 7.23 (2H, d), 7.40 (2H, t), 7.58 (3H, td), 7.78 (2H, d)
Process 2
Synthesis of 1-benzenesulfonyl-N- [2- (3-amidinophenoxy) ethyl] piperidine-4-carboxamide trifluoroacetate
568 mg (1.37 mmol) of 1-benzenesulfonyl-N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide was stirred in 10 ml of dioxane containing 4N hydrogen chloride, and 30% of hydrogen chloride was added thereto. After adding 3.5 ml of ethanol containing (w / v) and stirring at room temperature for 3 days, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 15 ml of ethanol solution containing 10% ammonia (w / v) at room temperature. For 2 days. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 533 mg (0.98 mmol) Yield 72%
MS (ESI, m / z) 430 (M +)
H-NMR (DMSO-d6) δ1.52 (2H, t), 1.72 (2H, d), 2.05-2.18 (1H, m), 2.30 (2H, t), 3.42 (2H, t), 3.60 (2H , d), 4.05 (2H, t), 7.26 (1H, d), 7.34 (1H, s), 7.38 (1H, d), 7.50 (1H, t), 7.62 (1H, d), 7.63-7.77 ( 5H, m), 8.00 (1H, t), 9.22 (4H, d)
Example 21
1-Benzyl-N- [2- (3-amidinophenoxy) ethyl] -piperidine-4-carboxamide Synthesis of ditrifluoroacetate
430 mg (1.58 mmol) of N- [2- (3-cyanophenoxy) ethyl] -piperidine-4-carboxamide was dissolved in 10 ml of dimethylformamide, 540 mg (3.93 mmol) of potassium carbonate, 0.16 ml of benzyl bromide (1 .31 mmol) was added and stirred at 50 ° C. for 13 hours. Ethyl acetate was used as an extraction solvent, and the mixture was treated according to a conventional method to obtain a crude 1-benzyl-N- [2- (3-cyanophenoxy) ethyl] piperidine-4-carboxamide. The crude product was stirred in 10 ml of dioxane containing 4N hydrogen chloride, and 3.5 ml of ethanol containing 30% hydrogen chloride (w / v) was added thereto, followed by stirring at room temperature for 3 days, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 20 ml of ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 2 days. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 532 mg (0.875 mmol) Yield 67%
MS (ESI, m / z) 381 (MH +)
H-NMR (DMSO-d6) δ 1.70 (2H, t), 1.90 (2H, t), 2.40 (1H, t), 2.90 (2H, t), 3.20-3.40 (2H, m), 3.42 (2H , t), 4.08 (2H, t), 4.15 (2H, brs), 7.28 (1H, d), 7.33 (1H, s), 7.34 (1H, d), 7.40-7.60 (5H, m), 8.26 ( 1H, brs), 9.30 (4H, d), 9.63-9.80 (1H, m)
Example 22
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (piperidin-1-yl) benzamide trifluoroacetate
Process 1
Synthesis of ethyl 4- (piperidin-1-yl) benzoate
2.16 g (13.1 mmol) of ethyl 4-aminobenzoate was dissolved in 20 ml of benzene, and 2.97 g (13.0 mmol) of 1,5-dibromopentane and 4.53 ml (26.0 mmol) of diisopropylethylamine were added. Heated to reflux for hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product of the title compound.
Yield 1.5 g (6.44 mmol) Yield 49%
H-NMR (CDCl3) δ1.37 (3H, t), 1.52-1.77 (6H, m), 3.26-3.37 (4H, m), 4.32 (2H, q), 6.85 (2H, d), 7.91 (2H , d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (piperidin-1-yl) benzamide trifluoroacetate
To 311 mg (1.33 mmol) of ethyl 4- (piperidin-1-yl) benzoate was added 5 ml of concentrated hydrochloric acid, and the mixture was stirred at 60 ° C. for 20 hours. The residue obtained by distilling off the solvent was dissolved in 10 ml of dichloromethane, 0.93 ml (6.65 mmol) of triethylamine, 279 mg (1.46 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. , 1-hydroxybenzotriazole 199 mg (1.46 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 264 mg (1.33 mmol) were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 310 mg (0.65 mmol) Yield 48%
MS (ESI, m / z) 367 (MH +)
H-NMR (DMSO-d6) δ1.58 (6H, br), 3.28 (4H, br), 3.62 (2H, dt), 4.18 (2H, t), 6.94 (2H, d), 7.30-7.41 (3H , m), 7.53 (1H, dd), 7.73 (2H, d), 8.42 (1H, br), 9.03 (2H, br), 9.28 (2H, br)
Example 23
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -1H-indole-5-carboxamide trifluoroacetate
237 mg (1.47 mmol) of 1H-indole-5-carboxylic acid was dissolved in 5 ml of dichloromethane, and 1.02 ml (7.35 mmol) of triethylamine, 309 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 1.62 mmol), 219 mg (1.62 mmol) of 1-hydroxybenzotriazole, and 291 mg (1.47 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 160 mg (0.29 mmol) Yield 20%
MS (ESI, m / z) 323 (MH +)
H-NMR (DMSO-d6) δ3.68 (2H, dt), 4.23 (2H, t), 6.52 (1H, br), 7.26-7.63 (8H, m), 8.14 (1H, br), 8.50-8.59 (1H, m), 9.12 (1H, br), 9.20 (1H, br), 9.20 (2H, br)
Example 24
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -1- (4-pyridyl) piperidine-4-carboxamide ditrifluoroacetate
Process 1
Synthesis of ethyl 1- (4-pyridyl) -piperidine-4-carboxylate
4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g (26.6 mmol) of ethyl piperidine-4-carboxylate, and 7.4 ml (53.2 mmol) of triethylamine were stirred in 130 ml of xylene at 130 ° C. for 24 hours. did. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 2.95 g (12.6 mmol) Yield 47%
MS (ESI, m / z) 235 (MH +)
H-NMR (CDCl3) δ1.25 (3H, t), 1.71-1.85 (2H, m), 2.00 (2H, d), 2.50-2.60 (1H, m), 2.90 (2H, t), 3.81 (2H , d), 4.20 (2H, q), 6.66 (2H, d), 8.26 (2H, d)
Process 2
Synthesis of 1- (4-pyridyl) -piperidine-4-carboxylic acid hydrochloride
2.95 g (12.6 mmol) of ethyl 1- (4-pyridyl) -piperidine-4-carboxylate was stirred in 100 ml of dioxane, 50 ml of 1N hydrochloric acid was added, and the mixture was stirred at 95 ° C. for 20 hours. To give the title compound.
Yield 3.21 g (11.5 mmol) Yield 91%
MS (ESI, m / z) 207 (MH +)
H-NMR (DMSO-d6) δ1.54 (2H, t), 1.90 (2H, d), 2.60-2.70 (1H, m), 3.30 (2H, t), 4.10 (2H, d), 7.19 (2H , d), 8.20 (2H, d)
Process 3
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -1- (4-pyridyl) -piperidine-4-carboxamide
1- (4-pyridyl) -piperidine-4-carboxylic acid hydrochloride 412 mg (1.48 mmol), 3- (2-aminoethoxy) benzonitrile 350 mg (1.77 mmol), triethylamine 0.25 ml (1.77 mmol), 240 mg (1.77 mmol) of 1-hydroxybenzotriazole and 340 mg (1.77 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were stirred overnight at room temperature in 3 ml of dimethylformamide. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 470 mg (1.34 mmol) Yield 91%
MS (ESI, m / z) 351 (MH +)
H-NMR (DMSO-d6) δ1.52 (2H, dd), 1.68 (2H, d), 2.38-2.45 (1H, m), 2.80 (2H, t), 3.40 (2H, dd), 3.90 (2H , d), 4.08 (2H, t), 6.80 (2H, d), 7.31 (1H, d), 7.40 (1H, d), 7.42 (1H, s), 7.51 (1H, t), 8.09 (1H, t), 8.13 (2H, d)
Process 4
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -1- (4-pyridyl) piperidine-4-carboxamide ditrifluoroacetate
460 mg (1.31 mmol) of N- [2- (3-cyanophenoxy) ethyl] -1- (4-pyridyl) -piperidine-4-carboxamide containing 30% hydrogen chloride (w / v) 10 ml of ethanol was added After stirring at room temperature for 7 days, the residue obtained by distilling off the solvent under reduced pressure was dissolved in 10 ml of an ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 31 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 402 mg (0.675 mmol) Yield 52%
MS (ESI, m / z) 368 (MH +)
H-NMR (DMSO-d6) δ1.57 (2H, dd), 1.82 (2H, dd), 2.51-2.60 (1H, m), 3.10 (2H, t), 3.40 (2H, t), 4.09 (2H , t), 4.23 (2H, d), 7.18 (2H, d), 7.25 (1H, d), 7.20 (1H, s), 7.40 (1H, d), 7.57 (1H, t), 8.02 (2H, t), 9.17 (4H, t)
Example 25
Synthesis of 4-benzoyl-N- [2- (3-amidinophenoxy) ethyl] benzamide trifluoroacetate
257 mg (1.14 mmol) of 4-benzoylbenzoic acid was dissolved in 10 ml of dichloromethane, 0.48 ml (3.42 mmol) of triethylamine, 240 mg (1.25 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1-hydroxybenzotriazole (169 mg, 1.25 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride (226 mg, 1.14 mmol) were added, and the mixture was stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 20 mg (0.04 mmol) Yield 4%
MS (ESI, m / z) 388 (MH +)
H-NMR (DMSO-d6) δ 3.68 (2H, dt), 4.13 (2H, t), 7.27-7.44 (4H, m), 7.54 (1H, dd), 7.57 (1H, d), 7.59 (2H , d), 7.75 (2H, d), 7.81 (2H, d), 8.01 (1H, d), 8.91 (1H, t), 9.10 (2H, br), 9.29 (2H, br)
Example 26
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-dimethylaminobenzamide trifluoroacetate
204 mg (1.24 mmol) of 4-dimethylaminobenzoic acid was dissolved in 10 ml of dichloromethane, 0.52 ml (3.72 mmol) of triethylamine, 260 mg (1.36 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ), 1-hydroxybenzotriazole 184 mg (1.36 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 246 mg (1.24 mmol) were added and stirred for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 300 mg (0.68 mmol) Yield 55%
MS (ESI, m / z) 327 (MH +)
H-NMR (DMSO-d6) δ2.96 (6H, s), 3.62 (2H, dt), 4.17 (2H, t), 6.70 (2H, d), 7.32-7.43 (3H, m), 7.54 (1H , dd), 7.74 (2H, d), 8.36 (1H, t), 9.05 (2H, br), 9.28 (2H, br)
Example 27
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -3- (2-aminoethoxy) benzamidine tritrifluoroacetate
After adding 10 ml of ethanol (w / v) containing 30% hydrogen chloride to 1.75 g (8.84 mmol) of 3- (2-aminoethoxy) benzonitrile and stirring at room temperature for 22 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in 10 ml of ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 31 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 134 mg (0.195 mmol) Yield 2.2%
MS (ESI, m / z) 342 (MH +)
H-NMR (DMSO-d6) δ3.20-3.23 (2H, m), 3.81-3.85 (2H, t), 4.24 (2H, dd), 4.38 (2H, dd), 7.25-7.40 (4H, m) , 7.50-7.60 (4H, m), 8.18 (2H, brs), 9.60 (4H, t)
Example 28
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-benzylbenzamide trifluoroacetate
780 mg (3.45 mmol) of 4-benzoylbenzoic acid was dissolved in 10 ml of acetic acid, 100 mg of palladium-carbon and 0.1 ml of concentrated sulfuric acid were added, and the mixture was stirred for 18 hours in the presence of medium pressure hydrogen. After distilling off the solvent, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was dissolved in dichloromethane (10 ml). Triethylamine (0.73 ml, 5.2 mmol), 1- (3-dimethylamino) Propyl) -3-ethylcarbodiimide hydrochloride 220 mg (1.15 mmol), 1-hydroxybenzotriazole 155 mg (1.15 mmol), 3- (2-aminoethoxy) benzonitrile hydrochloride 206 mg (1.04 mmol) were added, and 18 Stir for hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue obtained was obtained in the same manner as in Example 1, step 6. Obtained.
Yield 150 mg (0.31 mmol) Yield 9%
MS (ESI, m / z) 374 (MH +)
H-NMR (DMSO-d6) δ3.65 (2H, dt), 3.99 (2H, s), 4.20 (2H, t), 7.15-7.41 (10H, m), 7.53 (1H, dd), 7.78 (2H , d), 8.66 (1H, t), 9.14 (2H, br), 9.27 (2H, br)
Example 29
N- [2- (3-amidinophenoxy) ethyl] -4- (piperazine-1-carbonyl) benzamide ditrifluoroacetate and
4- [N- [2- (3-Amidinophenoxy) ethyl] carbamoyl] benzoic acid ethyl ester Synthesis of ditrifluoroacetate
Process 1
Synthesis of t-butyl 4- (4-methoxycarbonylbenzoyl) piperazine-1-carboxylate 4.93 g (26.5 mmol) of piperazine-1-carboxylic acid t-butyl and 4.8 ml (34.5 mmol) of triethylamine were added to dimethylformamide. The mixture was stirred in 50 ml under ice-cooling, and 5.25 g (26.5 mmol) of terephthalic acid monomethyl ester chloride was slowly added thereto and stirred for 16 hours. After returning to room temperature, the reaction mixture was diluted with 1N hydrochloric acid, extracted with ethyl acetate, and treated according to a conventional method to obtain the title compound.
Yield 7.08 g (20.3 mmol) Yield 77%
MS (ESI, m / z) 349 (MH +)
H-NMR (CDCl3) δ1.47 (9H, s), 3.25-3.60 (6H, m), 3.60-3.80 (2H, m), 3.94 (3H, s), 7.46 (2H, d), 8.09 (2H , d)
Process 2
Synthesis of t-butyl 4- (4-carboxybenzoyl) piperazine-1-carboxylate
7.08 g (20.3 mmol) of t-butyl 4- (4-methoxycarbonylbenzoyl) piperazine-1-carboxylate was stirred in 40 ml of methanol and 40 ml of THF, and 51 ml (51 mmol) of 1N aqueous sodium hydroxide solution was added, followed by 80 ° C. For 20 minutes. The reaction solution was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate to give the title compound according to a conventional method.
Yield 6.78 g (20.3 mmol) Yield 100%
MS (ESI, m / z) 335 (MH +)
H-NMR (CDCl3) δ1.41 (9H, s), 3.20-3.50 (6H, m), 3.52-3.70 (2H, m), 7.49 (2H, d), 8.01 (2H, d)
Process 3
Synthesis of t-butyl 4- [4- [N- [2- (3-cyanophenoxy) ethyl] carbamoyl] benzoyl] piperazine-1-carboxylate
4- (4-Carboxybenzoyl) piperazine-1-carboxylic acid t-butyl 1.60 g (4.8 mmol), 3- (2-aminoethoxy) benzonitrile 1.58 g (8.0 mmol), triethylamine 1.67 ml ( 12 mmol), 1-hydroxybenzotriazole (650 mg, 4.8 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (920 mg, 4.8 mmol) were stirred in dimethylformamide (20 ml) at room temperature overnight. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 1.44 g (3.02 mmol) Yield 63%
MS (ESI, m / z) 479 (MH +)
H-NMR (CDCl3) δ 1.47 (9H, s), 3.20-3.60 (6H, m), 3.62-3.80 (2H, m), 3.91 (2H, t), 4.20 (2H, t), 6.60 (1H , brs), 7.15 (1H, d), 7.18 (1H, s), 7.28 (1H, d), 7.39 (1H, t), 7.49 (2H, d), 7.82 (2H, d)
Process 4
N- [2- (3-amidinophenoxy) ethyl] -4- (piperazine-1-carbonyl) benzamide ditrifluoroacetate and
4- [N- [2- (3-Amidinophenoxy) ethyl] carbamoyl] benzoic acid ethyl ester Synthesis of ditrifluoroacetate
4- [4- [N- [2- (3-Cyanophenoxy) ethyl] carbamoyl] benzoyl] -piperazine-1-carboxylate 1.44 g (3.02 mmol) of dioxane containing 4N hydrogen chloride 5 ml Then, 5 ml of ethanol containing 30% hydrogen chloride (w / v) was added thereto, and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the resulting residue contained 10% ammonia (w / v ) Dissolved in 5 ml of ethanol solution and stirred at room temperature for 22 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
N- [2- (3-Amidinophenoxy) ethyl] -4- (piperazine-1-carbonyl) benzamide ditrifluoroacetate
Yield 145 mg (0.23 mmol) Yield 7.7%
MS (ESI, m / z) 396 (MH +)
H-NMR (DMSO-d6) δ 3.10-3.23 (6H, m), 3.40-3.80 (2H, m), 3.65 (2H, t), 4.23 (2H, t) 7.33 (1H, d), 7.38 ( 2H, d), 7.50 (1H, d), 7.55 (2H, d), 7.95 (2H, d), 8.86 (1H, t), 9.00 (2H, brs), 9.20 (4H, d)
4- [N- [2- (3-Amidinophenoxy) ethyl] carbamoyl] benzoic acid ethyl ester ditrifluoroacetate
MS (FAB, m / z) 356 (MH +)
H-NMR (DMSO-d6) δ1.34 (3H, t), 3.68 (2H, dt), 4.23 (2H, t), 4.38 (2H, q), 7.35-7.40 (3H, m), 7.51 (1H , t), 7.97 (2H, d), 8.02 (2H, d), 8.92 (1H, t), 9.10 (2H, br), 9.26 (2H, br)
Example 30
4- (4-Acetimidoylpiperazine-1-carbonyl) -N- [2- (3-amidinophenoxy) ethyl] benzamide Synthesis of ditrifluoroacetate
N- [2- (3-amidinophenoxy) ethyl] -4- (piperazine-1-carbonyl) benzamide 597 mg (1.51 mmol) of ditrifluoroacetate was dissolved in 12 ml of ethanol, 1 ml (7.8 mmol) of triethylamine, Ethyl acetimidate hydrochloride (380 mg, 0.764 mmol) was added, and the mixture was stirred at room temperature for 2 days. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 23.3 mg (0.035 mmol) Yield 2.3%
MS (ESI, m / z) 437 (MH +)
H-NMR (DMSO-d6) δ 2.30 (3H, brs), 3.10-3.25 (2H, m), 3.40-3.80 (8H, m), 4.24 (2H, t), 7.30 (1H, d), 7.39 (2H, d), 7.52 (1H, d), 7.55 (2H, d), 7.95 (2H, d), 8.70 (1H, t), 8.87 (2H, brs), 9.22 (4H, d)
Example 31
N- [2- (3-Amidinophenoxy) ethyl] -4-aminobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-aminobenzamide
4.00 g (20.4 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride was dissolved in 50 ml of dimethylformamide, 6.2 ml (43.8 mmol) of triethylamine, 2.00 g (14.6 mmol) of paraaminobenzoic acid, 1.98 g (14.6 mmol) of 1-hydroxybenzotriazole and 2.80 g (14.6 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added at 0 ° C. and stirred overnight at room temperature. . The title compound was obtained by treating with ethyl acetate as an extraction solvent according to a conventional method and then purifying by silica gel chromatography.
Yield 1.69 g (6.01 mmol) Yield 29%
MS (ESI, m / z) 282 (MH +)
H-NMR (DMSO-d6) δ3.58 (2H, q), 4.15 (2H, t), 5.61 (2H, br), 6.54 (2H, d), 7.32 (1H, d), 7.38 (1H, d ), 7.44 (1H, s), 7.58 (2H, d), 7.95 (1H, s), 8.19 (1H, t)
Process 2
N- [2- (3-Amidinophenoxy) ethyl] -4-aminobenzamide Synthesis of ditrifluoroacetate
The title compound was obtained in the same manner as in Step 1 of Example 1 using 110 mg (0.39 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-aminobenzamide as a starting material.
Yield 45.5 mg (0.087 mmol) Yield 22%
MS (ESI, m / z) 299 (MH +)
H-NMR (DMSO-d6) δ3.21 (2H, br), 4.38 (2H, dd), 7.19 (1H, s), 7.34 (1H, d), 7.36 (1H, s), 7.42-7.60 (5H , m), 8.42 (3H, br), 9.34 (2H, br), 9.54 (2H, br)
Example 32
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (phenylmethanesulfonylamino) benzamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (phenylmethanesulfonylamino) benzamide
670 mg (2.38 mmol) of 4-amino-N- [2- (3-cyanophenoxy) ethyl] benzamide was dissolved in 10 ml of dimethylformamide, 0.42 ml (2.38 mmol) of diisopropylethylamine, 454 mg of α-toluenesulfonyl chloride ( 2.38 mmol) was added at 0 ° C. and stirred for 13 hours. The title compound was obtained by treating in accordance with a conventional method using ethyl acetate as an extraction solvent. Yield 200 mg (0.46 mmol) Yield 19%
MS (ESI, m / z) 436 (MH +)
H-NMR (CDCl3) δ 3.70 (2H, t), 4.10 (2H, t), 4.79 (2H, s), 7.10-7.19 (2H, m), 7.20-7.28 (2H, m), 7.30-7.40 (5H, m), 7.48 (2H, d), 7.51 (2H, d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (phenylmethanesulfonylamino) benzamide trifluoroacetate
N- [2- (3-cyanophenoxy) ethyl] -4- (phenylmethanesulfonylamino) benzamide 261 mg (0.6 mmol) containing 30% hydrogen chloride (w / v) 10 ml of ethanol was added for 3 days at room temperature. After stirring, the residue obtained by distilling off the solvent under reduced pressure was dissolved in 10 ml of ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 31 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 71.7 mg (0.127 mmol) Yield 21%
MS (ESI, m / z) 453 (MH +)
H-NMR (DMSO-d6) δ 3.69 (2H, t), 4.19 (2H, t), 4.53 (2H, s), 7.20-7.40 (11H, m), 7.84 (2H, d), 8.64 (1H , t), 9.10 (4H, d)
Example 33
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-phenoxybenzamide trifluoroacetate
296 mg (1.4 mmol) of 4-phenoxybenzoic acid was dissolved in 10 ml of dichloromethane, 0.56 ml (4.2 mmol) of triethylamine, 295 mg (1.5 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride , 1-hydroxybenzotriazole 208 mg (1.5 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 277 mg (1.4 mmol) were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got. Yield 360 mg (0.74 mmol) Yield 53%
MS (ESI, m / z) 376 (MH +)
H-NMR (DMSO-d6) δ3.67 (2H, dt), 4.21 (2H, t), 7.01 (2H, d), 7.07 (2H, d), 7.18 (1H, d), 7.30-7.48 (5H , m), 7.53 (1H, dd), 7.88 (2H, d), 8.70 (1H, t), 9.23 (2H, br), 9.29 (2H, br)
Example 34
N- [2- (3-Amidinophenoxy) ethyl] -2- [N-methyl-N- (pyridin-4-yl) amino] acetamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of [N-methyl-N- (pyridin-4-yl) amino] ethyl acetate
4-chloropyridine (17 g, 113 mmol), (methylamino) ethyl acetate (17 g, 111 mmol) and triethylamine (47 ml, 333 mmol) were stirred in xylene (350 ml) at 130 ° C. for 24 hours. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 1.28 g (6.59 mmol) Yield 6%
H-NMR (CDCl3) δ 1.26 (3H, t), 3.09 (2H, s), 4.17 (3H, s), 4.24 (2H, q), 6.49 (2H, d), 8.25 (2H, d)
Process 2
Synthesis of [N-methyl-N- (pyridin-4-yl) amino] acetic acid hydrochloride
1.28 g (6.60 mmol) of ethyl [N-methyl-N- (pyridin-4-yl) amino] acetate was stirred in 30 ml of dioxane, 26 ml of 1N hydrochloric acid was added, and the mixture was stirred at 95 ° C. for 20 hours. Distilled under reduced pressure to give the title compound.
Yield 1.24 g (5.19 mmol) Yield 79%
H-NMR (DMSO-d6) δ 3.19 (3H, s), 4.48 (2H, s), 7.03 (2H, brs), 8.30 (2H, brs)
Process 3
N- [2- (3-Amidinophenoxy) ethyl] -2- [N-methyl-N- (pyridin-4-yl) amino] acetamide Synthesis of ditrifluoroacetate
[N-methyl-N- (pyridin-4-yl) amino] acetic acid hydrochloride 300 mg (1.26 mmol), 3- (2-aminoethoxy) benzonitrile 300 mg (1.51 mmol), triethylamine 0.21 ml (1. 51 mmol), 205 mg (1.51 mmol) of 1-hydroxybenzotriazole and 290 mg (1.51 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were stirred overnight at room temperature in 1.3 ml of dimethylformamide. did. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. This crude product was stirred in 2 ml of dioxane containing 4N hydrogen chloride, 2 ml of ethanol containing 30% hydrogen chloride (w / v) was added thereto, and the mixture was stirred at room temperature for 7 days, and the solvent was distilled off under reduced pressure. The residue was dissolved in 2 ml of ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 31 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 185 mg (0.281 mmol) Yield 22%
MS (ESI, m / z) 328 (MH +)
H-NMR (DMSO-d6) δ3.24 (3H, s), 3.50 (2H, t), 4.10 (2H, t), 4.30 (2H, s), 6.99 (2H, brs), 7.31 (1H, d ), 7.33 (1H, s), 7.40 (1H, d), 7.57 (1H, t), 8.25 (2H, brs), 8.56 (1H, t), 9.38 (4H, d)
Example 35
N- [2- (3-Amidinophenoxy) ethyl] -4-[(pyridin-4-yl) amino] benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of ethyl 4-[(pyridin-4-yl) amino] benzoate
4.57 g (31 mmol) of 4-chloropyridine and 5.03 g (31 mmol) of ethyl 4-aminobenzoate were dissolved in 100 ml of xylene, 12.7 ml (92 mmol) of triethylamine was added, and the mixture was heated to reflux for 50 hours. After distilling off the solvent, the reaction solution was diluted with water and extracted with dichloromethane. After washing with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Yield 360 mg (1.49 mmol) Yield 5%
H-NMR (CDCl3) δ 1.40 (3H, t), 4.37 (2H, q), 6.95 (2H, dd), 7.19 (2H, dd), 8.03 (2H, dd), 8.38 (2H, dd)
Process 2
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-[(pyridin-4-yl) amino] benzamide
180 mg (0.743 mmol) of ethyl 4-[(pyridin-4-yl) amino] benzoate was dissolved in 5 ml of concentrated hydrochloric acid and stirred at 70 ° C. for 15 hours. After the solvent was distilled off, the residue was dissolved in 5 ml of dichloromethane, 0.23 ml (1.64 mmol) of triethylamine, 156 mg (0.82 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole 208 mg (0.82 mmol) and 199 mg (0.82 mmol) of 3- (2-aminoethoxy) benzonitrile hydrobromide were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the title compound. It was.
Yield 99 mg (0.27 mmol) Yield 37%
H-NMR (CD3OD) δ3.78 (2H, dt), 4.23 (2H, t), 7.06 (1H, dd), 7.25-7.40 (6H, m), 7.85 (2H, dd), 8.19 (2H, dd )
Process 3
N- [2- (3-Amidinophenoxy) ethyl] -4-[(pyridin-4-yl) amino] benzamide Synthesis of ditrifluoroacetate
N- [2- (3-cyanophenoxy) ethyl] -4-[(pyridin-4-yl) amino] benzamide (95 mg, 0.27 mmol) was obtained in the same manner as in Example 1, step 6, to obtain the title compound. Yield 51 mg (0.08 mmol) Yield 32%
MS (ESI, m / z) 376 (MH +)
H-NMR (DMSO-d6) δ 3.68 (2H, dt), 4.24 (2H, t), 7.24 (2H, d), 7.30-7.37 (2H, m), 7.39-7.48 (3H, m), 7.53 (1H, dd), 7.98 (2H, d), 8.12-8.26 (1H, m), 8.34 (2H, d), 8.80-8.89 (1H, m), 9.16 (2H, br), 9.33 (2H, br )
Example 36
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N-methylcarbamoyl) benzamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (N-methylcarbamoyl) benzamide
4- [N- [2- (3-Cyanophenoxy) ethyl] carbamoyl] benzoic acid 150 mg (0.48 mmol), ethyl chloroformate 52 mg (0.48 mmol), triethylamine 0.5 ml (excess), 40% monomethylamine The title compound was obtained in the same manner as in Example 3, Step 2 using 3 ml of an aqueous solution.
Yield 87 mg (0.27 mmol) Yield 56%
H-NMR (CDCl3) δ 3.05 (3H, d), 3.90 (2H, dt), 4.20 (2H, t), 6.20 (1H, br), 6.61 (1H, br), 7.15 (1H, d), 7.17 (1H, s), 7.27 (1H, d), 7.39 (1H, t), 7.83 (4H, s)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (N-methylcarbamoyl) benzamide trifluoroacetate
The title compound was obtained in the same manner as in Step 3 of Example 3 using 83 mg (0.26 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4- (N-methylcarbamoyl) benzamide.
Yield 68 mg (0.15 mmol) Yield 58%
MS (ESI, m / z) 341 (MH +)
H-NMR (DMSO-d6) δ 2.80 (3H, d), 3.70 (2H, dt), 4.20 (2H, t), 7.34 (1H, d), 7.39 (1H, d), 7.40 (1H, s ), 7.54 (1H, t), 7.88-7.94 (4H, m), 8.54 (1H, d), 8.82 (1H, t), 9.05 (2H, br), 9.28 (2H, br)
Example 37
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-phenylbenzamide trifluoroacetate
132 mg (0.67 mmol) of 4-phenylbenzoic acid was dissolved in 10 ml of dichloromethane, 0.28 ml (2.0 mmol) of triethylamine, 141 mg (0.73 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1-hydroxybenzotriazole 59 mg (0.59 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 132 mg (0.67 mmol) were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got. Yield 30 mg (0.08 mmol) Yield 8%
MS (ESI, m / z) 360 (MH +)
H-NMR (DMSO-d6) δ 3.89 (2H, dt), 4.25 (2H, t), 7.31-7.45 (3H, m), 7.48 (2H, d), 7.52 (1H, d), 7.54 (1H , dd), 7.73 (2H, d), 7.78 (2H, d), 7.98 (2H, d), 8.82 (1H, t), 9.15 (2H, br), 9.33 (2H, br)
Example 38
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-cyclohexylbenzamide trifluoroacetate
Into 136 mg (0.67 mmol) of 4-cyclohexylbenzoic acid, 5 ml of dimethylformamide, and 0.07 ml (1.34 mmol) of N-methylmorpholine, 0.10 ml (0.67 mmol) of ethyl chloroformate was added under ice cooling and stirred for 30 minutes. . Under the same temperature, 132 mg (0.67 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride was added, and the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give the title compound according to the same procedure as in Example 1, step 6. It was.
Yield 40 mg (0.08 mmol) Yield 12%
MS (ESI, m / z) 366 (MH +)
H-NMR (DMSO-d6) δ1.18-1.51 (5H, m), 1.45 (9H, s), 1.65-1.78 (5H, m), 2.52-2.63 (1H, m), 3.65 (2H, dt) , 4.21 (2H, t), 7.25-7.37 (3H, m), 7.39 (2H, d), 7.54 (1H, dd), 7.79 (2H, d), 8.68 (1H, t), 9.15 (2H, br ), 9.34 (2H, br)
Example 39
N- [2- (3-Amidinophenoxy) ethyl] -4- (piperazine-1-sulfonyl) benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of t-butyl 4- (4-methoxycarbonylbenzenesulfonyl) -piperazine-1-carboxylate
14.Iodine-benzenesulfonyl chloride was dissolved in 10.67 g (57.3 mmol) of piperazine-1-carboxylic acid in 180 ml of dimethylformamide and 10 ml (57.3 mmol) of diisopropylethylamine and 20 ml of dimethylformamide. 3 g (57.3 mmol) was added at 0 ° C. and stirred for 5 hours. Ethyl acetate was used as an extraction solvent, and the mixture was treated according to a conventional method to obtain a crude t-butyl 4- (4-iodobenzenesulfonyl) -piperazine-1-carboxylate. This crude product was dissolved in 150 ml of dimethylformamide, 750 mg (3.5 mmol) of palladium (II) acetate, 55 ml (1.39 mol) of methanol and 19 ml (139 mmol) of triethylamine were added and heated at 90 ° C. for 23 hours in the presence of carbon monoxide. , Stirred. The crude product of the title compound was obtained by treating in accordance with a conventional method using ethyl acetate as an extraction solvent. Subsequently, it was purified by silica gel column chromatography.
Yield 4.30 g (11.2 mmol) Yield 20%
H-NMR (CDCl3) δ1.42 (9H, s), 2.98 (4H, t), 3.51 (4H, t), 3.97 (3H, s), 7.82 (2H, d), 8.20 (2H, d)
Process 2
Synthesis of t-butyl 4- (4-carboxybenzenesulfonyl) -piperazine-1-carboxylate 4.30 g (11.2 mmol) of t-butyl 4- (4-methoxycarbonylbenzenesulfonyl) -piperazine-1-carboxylic acid The mixture was stirred in 15 ml of methanol and 15 ml of THF, 17 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at 60 ° C. The reaction mixture was evaporated under reduced pressure, 1N hydrochloric acid was added, and ethyl acetate was used as the extraction solvent, and the mixture was treated in the usual manner to give the title compound.
Yield 1.41 g (3.8 mmol) Yield 34%
MS (ESI, m / z) 398 (M + Na +)
H-NMR (CDCl3) δ1.41 (9H, s), 3.02 (4H, t), 3.52 (4H, t), 7.84 (2H, d), 8.24 (2H, d)
Process 3
Synthesis of t-butyl 4- [4- [N- [2- (3-cyanophenoxy) ethyl] carbamoyl] benzenesulfonyl] -piperazine-1-carboxylate
(4-Carboxybenzenesulfonyl) piperazine-1-carboxylic acid t-butyl 1.41 g (3.79 mmol) was stirred in dimethylformamide, 1.3 ml (9.25 mmol) of triethylamine and 0.38 ml of ethyl chloroformate under ice-cooling. After adding (3.95 mmol) and stirring for 5 minutes, 1.02 g (4.61 mmol) of 3- (2-aminoethoxy) benzonitrile was added. After returning to room temperature and stirring for 2 hours, the mixture was diluted with 1N hydrochloric acid, extracted with ethyl acetate, and treated according to a conventional method to obtain the title compound.
Yield 1.88 g (3.66 mmol) Yield 97%
MS (ESI, m / z) 537 (M + Na +)
H-NMR (CDCl3) δ 1.40 (9H, s), 2.97 (4H, t), 3.49 (4H, t), 3.91 (2H, dd), 4.19 (2H, t), 7.03 (1H, t), 7.14 (1H, d), 7.17 (1H, s), 7.27 (1H, d), 7.38 (1H, d), 7.78 (2H, d), 7.98 (2H, d)
Process 4
N- [2- (3-Amidinophenoxy) ethyl] -4- (piperazine-1-sulfonyl) benzamide Synthesis of ditrifluoroacetate
[4- [N- [2- (3-Cyanophenoxy) ethyl] carbamoyl] benzenesulfonyl] piperazine-1-carboxylate 1.88 g (3.66 mmol) of dioxane containing 4N hydrogen chloride 0.92 ml (3.66 mmol), and 30 ml of hydrogen chloride was added thereto (w / v) 4 ml of ethanol was added and stirred at room temperature for 6 days. The solvent was distilled off under reduced pressure, and the resulting residue contained 10% ammonia. (W / v) dissolved in 5 ml of ethanol solution and stirred at room temperature for 17 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 736 mg (1.12 mmol) Yield 31%
MS (ESI, m / z) 432 (MH +)
H-NMR (DMSO-d6) δ 3.12 (4H, d), 3.20 (4H, d), 3.70 (2H, dd), 4.22 (2H, t), 7.32 (1H, d), 7.38 (1H, s ), 7.40 (1H, d), 7.54 (1H, t), 7.90 (2H, d), 8.14 (2H, d), 8.60 (1H, brs), 8.95 (1H, brs), 9.15 (4H, d)
Example 40
4- (4-Acetimidoylpiperazine-1-sulfonyl) -N- [2- (3-amidinophenoxy) ethyl] benzamide Synthesis of ditrifluoroacetate
N- [2- (3-Amidinophenoxy) ethyl] -4- (piperazine-1-sulfonyl) benzamide 240 mg (0.364 mmol) of ditrifluoroacetate was dissolved in 3 ml of ethanol, and 0.27 ml (1.89 mmol) of triethylamine was dissolved. ), Ethyl acetimidate hydrochloride (95 mg, 0.764 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 113 mg (0.161 mmol) Yield 44%
MS (ESI, m / z) 473 (MH +)
H-NMR (DMSO-d6) δ2.18 (3H, s), 3.05-3.18 (4H, m), 3.58-3.68 (4H, m), 3.75 (2H, t), 4.44 (2H, t), 7.31 (1H, d), 7.39 (1H, s), 7.41 (1H, d), 7.54 (1H, t), 7.88 (2H, d), 8.12 (2H, d), 8.68 (1H, s), 9.05 ( 1H, t), 9.28 (4H, d)
Example 41
N- [2- (3-Amidinophenoxy) ethyl] -4-[(pyridin-4-yl) methyl] benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 4- (4-iodobenzyl) pyridine
4-Benzylpyridine 5.0 g (30 mmol) was dissolved in acetic acid 30 ml, concentrated sulfuric acid 3.53 ml (65 mmol), iodine 2.99 g (11.8 mmol), sodium iodate 1.17 g (5.9 mmol) was added, Stir at 70 ° C. for 20 hours. After cooling, 0.15 g of sodium metaperiodate was added and distilled off under reduced pressure. Water was added, washed with dichloromethane, 1N sodium hydroxide was added, and dichloromethane extraction was performed twice. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 2.7 g (9.2 mmol) Yield 31%
H-NMR (CDCl3) δ3.91 (2H, s), 6.92 (2H, d), 7.07 (2H, d), 7.64 (2H, d), 8.50 (2H, d)
Process 2
Synthesis of methyl 4-[(pyridin-4-yl) methyl] benzoate
1.03 g (3.49 mmol) of 4- (4-iodobenzyl) pyridine was dissolved in 15 ml of dimethylformamide, 39 mg (0.18 mmol) of palladium acetate, 0.97 ml (6.98 mmol) of triethylamine, 2.82 ml of methanol (69 8 mmol), and the mixture was stirred at 70 ° C. for 6 hours in the presence of carbon monoxide. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Yield 630 mg (2.78 mmol) Yield 79%
H-NMR (CDCl3) δ3.91 (3H, s), 4.02 (2H, s), 7.08 (2H, d), 7.24 (2H, d), 7.98 (2H, d), 8.51 (2H, dd)
Process 3
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-[(pyridin-4-yl) methyl] benzamide
262 mg (1.15 mmol) of methyl 4-[(pyridin-4-yl) methyl] benzoate was dissolved in 5 ml of concentrated hydrochloric acid and stirred at 70 ° C. for 15 hours. The residue obtained by distilling off the solvent was dissolved in 5 ml of dichloromethane, 0.24 ml (1.73 mmol) of triethylamine, and 243 mg (1.27 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. , 1-hydroxybenzotriazole 172 mg (1.27 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 308 mg (1.27 mmol) were added, and the mixture was stirred for 15 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the title compound. It was.
Yield 320 mg (0.90 mmol) Yield 78%
H-NMR (CDCl3) δ 3.89 (2H, dt), 4.02 (2H, s), 4.18 (2H, t), 6.46-6.57 (1H, m), 7.16 (2H, br), 7.25 (2H, d ), 7.27 (2H, d), 7.39 (1H, dd), 7.74 (2H, d), 8.51 (2H, dd)
Process 4
N- [2- (3-Amidinophenoxy) ethyl] -4-[(pyridin-4-yl) methyl] benzamide Synthesis of ditrifluoroacetate
Starting from 218 mg (0.61 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-[(pyridin-4-yl) methyl] benzamide, the title compound was prepared in the same manner as in Example 1, Step 6. Got.
Yield 170 mg (0.45 mmol) Yield 74%
MS (ESI, m / z) 375 (MH +)
H-NMR (DMSO-d6) δ 3.65 (2H, dt), 4.20 (2H, s), 4.21 (2H, t), 7.22-7.43 (5H, m), 7.47 (1H, dd), 7.60 (2H , d), 7.83 (2H, dd), 8.65 (3H, br), 9.08 (2H, br), 9.28 (2H, br)
Example 42
N- [2- (3-Amidinophenoxy) ethyl] -4-[(piperidin-4-ylidene) methyl] benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of methyl 4- (diethoxyphosphorylmethyl) benzoate
To 2.29 g (10 mmol) of methyl 4- (bromomethyl) benzoate was added 6.64 g (40 mmol) of triethyl phosphite, and the mixture was stirred at 150 ° C. for 19 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound.
Yield 2.6 g (9 mmol) Yield 90%
H-NMR (CDCl3) δ1.25 (6H, t), 3.20 (2H, d), 4.02 (4H, dq), 7.39 (2H, d), 8.00 (2H, d)
Process 2
Synthesis of methyl 4-[[1- (t-butoxycarbonyl) piperidin-4-ylidene] methyl] benzoate
To 1.0 g (5.0 mmol) of 4-piperidone, 2.7 ml (20.0 mmol) of triethylamine, 1.84 g (8.45 mmol) of di-t-butyl carbonate and 30 ml of dichloromethane were added and stirred for 19 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-t-butoxycarbonyl-4-piperidone. Under ice-cooling, 80 ml of tetrahydrofuran and methyl 4- (diethoxyphosphorylmethyl) benzoate were added to 241 mg (6.0 mmol) of sodium hydride, stirred for 30 minutes, returned to room temperature, and stirred for 30 minutes. The crude 1-t-butoxycarbonyl-4-piperidone obtained above was added and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography to obtain the title compound.
Yield 1.26 g (3.8 mmol) Yield 76%
H-NMR (CDCl3) δ 1.48 (9H, s), 2.38 (2H, dd), 2.44 (2H, dd), 3.42 (2H, dd), 3.53 (2H, dd), 3.89 (3H, s), 6.39 (1H, br), 7.24 (2H, d), 7.98 (2H, d)
Process 3
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-[(1-t-butoxycarbonylpiperidin-4-ylidene) methyl] benzamide
6 ml of 1N sodium hydroxide and 18 ml of ethanol were added to 331 mg (1.0 mmol) of methyl 4-[(1-t-butoxycarbonylpiperidin-4-ylidene) methyl] benzoate and stirred for 18 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was cooled with ice to 5 ml of dimethylformamide, 0.22 ml (2.0 mmol) of N-methylmorpholine, 0.10 ml (1.0 mmol) of ethyl chloroformate. ) And stirred for 30 minutes. Under the same temperature, 243 mg (1.0 mmol) of 3- (2-aminoethoxy) benzonitrile hydrobromide was added, and the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 309 mg (0.67 mmol) Yield 67%
H-NMR (CDCl3) δ 1.48 (9H, s), 2.35 (2H, dd), 2.44 (2H, dd), 3.41 (2H, dd), 3.52 (2H, dd), 3.89 (2H, dt), 4.18 (2H, t), 6.37 (1H, br), 6.51-6.60 (1H, m), 7.17 (1H, br), 7.23-7.29 (1H, m), 7.39 (1H, dt), 7.74 (2H, d)
Process 4
N- [2- (3-Amidinophenoxy) ethyl] -4-[(piperidin-4-ylidene) methyl] benzamide Synthesis of ditrifluoroacetate
Using 230 mg (0.50 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-[(1-t-butoxycarbonylpiperidin-4-ylidene) methyl] benzamide as a starting material, Example 1 Step 6 The title compound was obtained according to the same procedure.
Yield 190 mg (0.31 mmol) Yield 63%
MS (ESI, m / z) 379 (MH +)
H-NMR (DMSO-d6) δ 2.42-2.68 (4H, m), 2.99-3.24 (4H, m), 3.68 (2H, dt), 4.22 (2H, t), 6.53 (1H, s), 7.24 -7.43 (6H, m), 7.56 (1H, t), 7.88 (2H, d), 8.77 (3H, br), 9.17 (2H, br), 9.30 (2H, br)
Example 43
N- [2- (3-Amidinophenoxy) ethyl] -4-[(piperidin-4-yl) methyl] benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4-[(1-t-butoxycarbonylpiperidin-4-yl) methyl] benzamide
To 434 mg (1.31 mmol) of methyl 4-[(1-t-butoxycarbonylpiperidin-4-ylidene) methyl] benzoate were added 95 mg of 10% palladium-carbon and 20 ml of methanol, and the mixture was stirred for 15 hours in the presence of hydrogen. After Celite filtration, the solvent was evaporated and the residue obtained was added 1N sodium hydroxide 4 ml and ethanol 6 ml and stirred for 18 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was cooled with ice to 5 ml of dimethylformamide, 0.22 ml (2.0 mmol) of N-methylmorpholine, and 0.10 ml (1.0 mmol) of ethyl chloroformate. ) And stirred for 30 minutes. Under the same temperature, 243 mg (1.0 mmol) of 3- (2-aminoethoxy) benzonitrile hydrobromide was added, and the mixture was returned to room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 296 mg (0.64 mmol) Yield 49%
H-NMR (CDCl3) δ 1.10-1.19 (2H, m), 1.45 (9H, s), 1.58-1.78 (3H, m), 2.59 (2H, d), 2.61-2.69 (2H, m), 3.89 (2H, dt), 4.00-4.13 (2H, m), 4.18 (2H, t), 6.46-6.55 (1H, m), 7.17 (2H, br), 7.18 (2H, d), 7.27 (1H, dt ), 7.71 (2H, d)
Process 2
N- [2- (3-Amidinophenoxy) ethyl] -4-[(piperidin-4-yl) methyl] benzamide Synthesis of ditrifluoroacetate
Similar to Step 6 of Example 1 using 230 mg (0.50 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-[(1-t-butoxycarbonylpiperidin-4-yl) methyl] benzamide as a raw material. To give the title compound.
Yield 190 mg (0.31 mmol) Yield 63%
MS (ESI, m / z) 381 (MH +)
H-NMR (DMSO-d6) δ 1.21-1.41 (2H, m), 1.62-1.74 (2H, m), 1.77-1.93 (1H, m), 2.59 (2H, d), 2.70-2.89 (2H, m), 3.05-3.32 (2H, m), 3.66 (2H, dt), 4.21 (2H, t), 7.28 (2H, d), 7.30-7.36 (1H, m), 7.37-7.43 (2H, m) 7.54 (1H, dd) 7.81 (2H, d), 8.18-8.36 (1H, m), 8.51-8.64 (2H, m), 8.68 (1H, t), 9.22 (2H, br), 9.29 (2H, br)
Example 44
N- [2- (3-Amidinophenoxy) ethyl] -4-[(1-acetimidoylpiperidin-4-ylidene) methyl] benzamide Synthesis of ditrifluoroacetate
9.9 mg (0.02 mmol) of N- [2- (3-amidinophenoxy) ethyl] -4-[(piperidin-4-ylidene) methyl] benzamide ditrifluoroacetate was dissolved in 2 ml of ethanol and 0. 02 ml (0.15 mmol) ethylacetimidate hydrochloride 4 mg (0.03 mmol) was added and stirred for 15 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 8.4 mg (0.01 mmol) Yield 79%
MS (ESI, m / z) 420 (MH +)
H-NMR (DMSO-d6) δ 2.31 (3H, s), 2.54-2.66 (3H, m), 2.68-2.75 (1H, m), 3.55-3.66 (4H, m), 3.67 (2H, dt) , 4.22 (2H, t), 6.50 (H, br), 7.29-7.44 (5H, m), 7.53 (1H, dd) 7.86 (2H, d), 8.56 (1H, br), 8.74 (1H, t) , 9.16 (1H, br), 9.20 (2H, br), 9.28 (2H, br)
Example 45
N- [2- (3-Amidinophenoxy) ethyl] -4-[(1-acetimidoylpiperidin-4-yl) methyl] benzamide Synthesis of ditrifluoroacetate
N- [2- (3-amidinophenoxy) ethyl] -4-[(piperidin-4-ylidene) methyl] benzamide 10 mg (0.02 mmol) of ditrifluoroacetate was dissolved in 2 ml of ethanol, and 0.02 ml of triethylamine ( 0.15 mmol) The title compound was obtained in the same manner as in Example 44 using 4 mg (0.03 mmol) of ethylacetimidate hydrochloride.
Yield 6 mg (0.01 mmol) Yield 56%
MS (ESI, m / z) 422 (MH +)
H-NMR (DMSO-d6) δ1.21-1.35 (2H, m), 1.59-1.62 (2H, m), 1.83-2.00 (1H, m), 2.24 (3H, s), 2.59 (2H, d) , 2.94-3.20 (2H, m), 3.66 (2H, dt), 3.80-3.92 (1H, m), 3.96-4.08 (2H, m), 4.21 (2H, t), 7.24-7.43 (5H, m) , 7.53 (1H, dd) 7.81 (2H, d), 8.48 (1H, br), 8.68 (1H, t), 9.03 (1H, br), 9.15 (2H, br) 9.28 (2H, br)
Example 46
N- [2- (3-Amidinophenoxy) ethyl] -4- (2-1H-imidazolyl) benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 4- (2-1H-imidazolyl) benzoic acid ethyl ester
500 mg (2.3 mmol) of 4- (2-imidazolin-2-yl) benzoic acid ethyl ester and 500 mg of 10% palladium-carbon were heated to reflux in 20 ml of toluene in an argon atmosphere for 9 hours. The reaction mixture was diluted with ethyl acetate and filtered through celite, and the filtrate was concentrated to give the title compound.
Yield 332 mg (1.5 mmol) Yield 67%
H-NMR (CDCl3) δ1.40 (3H, t), 4.40 (2H, q), 7.20 (2H, s), 7.90 (2H, d), 8.10 (2H, d)
Process 2
Synthesis of 4- (2-1H-imidazolyl) benzoic acid hydrochloride
160 mg (0.74 mmol) of 4- (2-1H-imidazolyl) benzoic acid ethyl ester was heated to reflux in 4 ml of hydrochloric acid and 8 ml of acetic acid. After 3 hours, the solvent was distilled off to obtain the title compound.
Yield 157 mg (0.70 mmol) Yield 94%
H-NMR (DMSO-d6) δ7.82 (2H, s), 8.15 (2H, d), 8.25 (2H, d)
Process 3
N- [2- (3-Amidinophenoxy) ethyl] -4- (2-1H-imidazolyl) benzamide Synthesis of ditrifluoroacetate
4- (2-1H-imidazolyl) benzoic acid hydrochloride 155 mg (0.7 mmol), 3- (2-aminoethoxy) benzonitrile hydrobromide 195 mg (0.8 mmol), 1- (3-dimethylaminopropyl) ) -3-ethylcarbodiimide hydrochloride 153 mg (0.8 mmol), 1-hydroxybenzotriazole hydrate (hydrous, 87%) 124 mg (0.8 mmol), triethylamine 300 mg (3.0 mmol) in dichloromethane at room temperature to 40 Stir at 2 ° C. for 2 days. The solvent was distilled off, 1N aqueous sodium hydroxide solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was suspended in chloroform and filtered, and the title compound was obtained from the filtered product in the same manner as in Example 1, Step 6.
Yield 78 mg (0.14 mmol) Yield 20%
MS (ESI, m / z) 350 (MH +)
H-NMR (DMSO-d6) δ3.70 (2H, dt), 4.23 (2H, t), 7.34 (1H, d), 7.40 (1H, d), 7.41 (1H, s), 7.54 (1H, t ), 7.72 (2H, s), 8.06 (2H, d), 8.16 (2H, d), 8.96 (1H, t), 9.16 (2H, br), 9.32 (2H, br)
Example 47
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-acetylbenzamide trifluoroacetate
223 mg (1.36 mmol) of 4-acetylbenzoic acid was dissolved in 10 ml of dichloromethane, 0.95 ml (6.80 mmol) of triethylamine, and 286 mg (1.50 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. , 202 mg (1.50 mmol) of 1-hydroxybenzotriazole and 269 mg (1.36 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 188 mg (0.58 mmol) Yield 43%
MS (ESI, m / z) 326 (MH +)
H-NMR (DMSO-d6) δ 2.62 (3H, s), 3.70 (2H, dt), 4.24 (2H, t), 7.31-7.42 (3H, m), 7.53 (1H, dd), 8.00 (4H , dd), 8.93 (1H, br), 9.11 (2H, br), 9.28 (2H, br)
Example 48
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4-chlorobenzamide trifluoroacetate
205 mg (1.02 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride was dissolved in 10 ml of dichloromethane, and 0.44 ml (3.12 mmol) of triethylamine and 217 mg (1.04 mmol) of 4-chlorobenzoyl chloride were cooled with ice. After stirring for 30 minutes, the mixture was returned to room temperature and stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was obtained in the same manner as in Example 1, step 6. The title compound was obtained.
Yield 170 mg (0.39 mmol) Yield 38%
MS (ESI, m / z) 317 (MH +)
H-NMR (DMSO-d6) δ 3.69 (2H, dt), 4.24 (2H, t), 7.34 (1H, dd), 7.40 (2H, br), 7.54 (1H, dd), 7.86 (2H, d ), 8.06 (2H, d), 8.99 (1H, br), 9.12 (2H, br), 9.28 (2H, br)
Example 49
N- [2- (3-Amidinophenoxy) ethyl] -4-guanidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 3-hydroxybenzamidine hydrochloride
5-Hydroxybenzonitrile (5 g, 42 mmol) was dissolved in 50 ml of ethanol containing 30% hydrogen chloride (w / v) and stirred overnight at room temperature. The residue obtained by evaporating the solvent was dissolved in 50 ml of an ethanol solution containing 30% ammonia (w / v) and stirred overnight at room temperature, and then the solvent was evaporated to obtain the title compound.
Yield 4.4 g (25.5 mmol) Yield 61%
Process 2
Synthesis of Nt-butoxycarbonyl-3-hydroxybenzamidine
3-hydroxybenzamidine hydrochloride 1 g (5.8 mmol), di-t-butyl dicarbonate 1.27 g (5.8 mmol), 4- (dimethylamino) pyridine 24 mg (0.2 mmol), triethylamine 1.30 g (12 8 mmol) was dissolved in 20 ml of dimethylformamide and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate, and then the organic layer was extracted with 1N aqueous sodium hydroxide solution. The aqueous layer was made weakly alkaline with concentrated hydrochloric acid and treated according to a conventional method using ethyl acetate as an extraction solvent to give the title compound.
Yield 458 mg (1.94 mmol) Yield 33%
H-NMR (DMSO-d6) δ1.45 (9H, s), 6.95 (1H, d), 7.25 (1H, t), 7.35 (1H, d), 7.38 (1H, s), 8.90 (2H, br ), 9.65 (1H, br)
Process 3
Synthesis of 3- (2-aminoethoxy) benzamidine dihydrochloride
Using Nt-butoxycarbonyl-3-hydroxybenzamidine and t-butyl-N- (2-bromoethyl) carbamate as starting materials, Nt-butoxycarbonyl-3- [2 -(T-Butoxycarbonylamino) ethoxy] benzamidine was obtained. The title compound was obtained in the same manner as in Example 1, Step 3 without purification.
H-NMR (DMSO-d6) δ3.20 (2H, t), 4.35 (2H, t), 7.34 (1H, d), 7.44-7.60 (3H, m), 8.36 (3H, br), 9.28 (2H , br), 9.50 (2H, br)
Process 4
N- [2- (3-Amidinophenoxy) ethyl] -4-guanidinobenzamide Synthesis of ditrifluoroacetate
4-guanidinobenzoic acid hydrochloride 152 mg (0.7 mmol), 3- (2-aminoethoxy) benzamidine dihydrochloride 166 mg (0.66 mmol), triethylamine 142 mg (1.4 mmol), 1-hydroxybenzotriazole (containing water, 87 %) 110 mg (0.7 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 134 mg (0.7 mmol) were stirred in 3 ml of dimethylformamide at room temperature overnight. After distilling off the solvent under reduced pressure, the residue was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, containing 0.1% trifluoroacetic acid (v / v), water and The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilizing the fraction of interest.
Yield 172 mg (0.3 mmol) Yield 46%
MS (ESI, m / z) 341 (MH +)
H-NMR (DMSO-d6) δ3.65 (2H, dt), 4.20 (2H, t), 7.28-7.42 (5H, m), 7.53 (1H, t), 7.70 (4H, brs), 7.93 (2H , d), 8.78 (1H, t), 9.20 (2H, br), 9.30 (2H, br), 10.15 (1H, s)
Example 50
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (1-phenoxycarbonyl-4-piperidyloxy) benzamide trifluoroacetate
N- [2- (3-cyanophenoxy) ethyl] -4- (1-t-butoxycarbonyl-4-piperidyloxy) benzamide was obtained by reacting 4N hydrogen chloride with dioxane and ethanol. [2- [4- (4-Piperidyloxy) benzoylamino] ethoxy] benzimidate ethyl dihydrochloride 96.4 mg (0.221 mmol), phenyl chloroformate 70.0 mg (0.447 mmol), diisopropylethylamine 742 mg (6 .07 mmol) was reacted in 15 ml of dichloromethane, then amidated with ethanol containing (w / v) 10% ammonia according to a conventional method, and reverse-phase high-speed using octadodecyl group chemically bonded silica gel as a filler. Subject to liquid chromatography and contain 0.1% trifluoroacetic acid (V / v) The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 54.5 mg (0.0885 mmol) Yield 40.0%
MS (ESI, m / z) 503 (MH +)
H-NMR (DMSO-d6) δ 1.60-2.07 (4H, m), 3.23-4.85 (6H, m), 4.10-4.21 (2H, m), 4.63-4.80 (1H, m), 7.03-7.58 ( 11H, m), 7.82 (2H, d), 8.55 (1H, t), 9.05 (2H, brs), 9.23 (2H, brs)
Example 51
(3S) -3- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butyric acid ditrifluoroacetate and
Synthesis of ethyl (3S) -3- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butyrate ditrifluoroacetate
Process 1
Synthesis of benzyl (3S) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butyrate
970 mg (3.0 mmol) of Nt-butoxycarbonyl-L-aspartic acid-β-benzyl ester and 0.42 ml (3.0 mmol) of triethylamine were dissolved in 15 ml of tetrahydrofuran, and 0.29 ml of ethyl chloroformate (3 0.0 mmol) was added and stirred for 20 minutes. The generated precipitate was removed by suction filtration, and 3 g of ice and 227 mg (6.0 mmol) of sodium borohydride were added to the filtrate under ice cooling, followed by stirring for 1.5 hours. 10 ml of 1N aqueous hydrogen chloride solution was added thereto, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. The oily residue thus obtained was dissolved in 12 ml of tetrahydrofuran, 288 mg (2.41 mmol) of 3-cyanophenol, 690 mg (2.63 mmol) of triphenylphosphine, 1.05 g (2. 41 mmol) was added and stirred overnight at room temperature. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 455 mg (1.11 mmol) Yield 37%
H-NMR (CDCl3) δ 1.46 (9H, s), 2.79 (2H, d), 4.00 (1H, dd), 4.06 (1H, dd), 4.41 (1H, br), 5.13 (2H, s), 5.56 (1H, br), 7.05-7.18 (4H, m), 7.21-7.38 (5H, m)
Process 2
Synthesis of benzyl (3S) -3- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butyrate
455 mg (1.1 mmol) of benzyl (3S) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butyrate was dissolved in 5 ml of 4N hydrogen chloride in dioxane and stirred at 0 ° C. for 6 hours. The oily residue obtained by distilling off the solvent was dissolved in 5 ml of dichloromethane, and 276 mg (1.67 mmol) of 4-cyanobenzoic acid chloride and 0.31 ml (2.22 mmol) of triethylamine were added under ice cooling, followed by stirring at room temperature overnight. did. The crude product was obtained by treating in accordance with a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 260 mg (0.59 mmol) Yield 53%
H-NMR (CDCl3) δ 2.86 (1H, dd), 2.95 (1H, dd), 4.12 (1H, dd), 4.20 (1H, dd), 4.85 (1H, br), 5.16 (2H, s), 7.09 (1H, d), 7.11 (1H, dd), 7.24-7.40 (7H, m), 7.72 (2H, d), 7.83 (2H, d)
Process 3
Synthesis of ethyl (3S) -3- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butyrate ditrifluoroacetate
260 mg (0.59 mmol) of benzyl (3S) -3- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butyrate is added to 5 ml of ethanol containing 30% hydrogen chloride (w / v) at room temperature. And stirred overnight. Subsequently, after the solvent was distilled off under reduced pressure, it was dissolved in 5 ml of an ethanol solution containing 10% ammonia (w / v) at room temperature and stirred at room temperature overnight. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 113 mg (0.176 mmol) Yield 30%
MS (ESI, m / z) 412 (MH +)
H-NMR (DMSO-d6) δ 1.15 (3H, t), 2.82 (2H, d), 4.07 (2H, q), 4.12 (1H, dd), 4.24 (1H, dd), 4.72 (1H, br ), 7.33 (1H, d), 7.39 (1H, s), 7.40 (1H, d), 7.54 (1H, dd), 7.91 (2H, d), 8.02 (2H, d), 8.84 (1H, d) , 9.16 (2H, s), 9.28 (4H, s), 9.42 (2H, s)
Process 4
Synthesis of (3S) -3- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butyric acid ditrifluoroacetate
Ethyl (3S) -3- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butyric acid 338 mg (0.528 mmol) of ditrifluoroacetate was dissolved in 10 ml of concentrated hydrochloric acid and stirred at 40 ° C. for 6 hours. . The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilizing the fraction of interest.
Yield 41 mg (0.067 mmol) Yield 13%
MS (ESI, m / z) 384 (MH +)
H-NMR (DMSO-d6) δ 2.74 (2H, d), 4.13 (1H, dd), 4.24 (1H, dd), 4.69 (1H, ddt), 7.35 (1H, d), 7.40 (1H, d ), 7.41 (1H, s), 7.55 (1H, dd), 7.91 (2H, d), 8.03 (2H, d), 8.81 (1H, d), 9.20 (2H, s), 9.28 (2H, s) , 9.33 (2H, s), 9.43 (2H, s)
Example 52
Synthesis of ethyl (3R) -4- (3-amidinophenoxy) -3- [4- (piperidin-4-yl) methylbenzoylamino] butyrate ditrifluoroacetate
Process 1
Synthesis of benzyl (3R) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butyrate
Nt-butoxycarbonyl-D-aspartic acid-β-benzyl ester 3.23 g (10.0 mmol) and triethylamine 1.39 ml (10.0 mmol) were dissolved in tetrahydrofuran 50 ml, and ice-cooled ethyl chloroformate 0.96 ml (10.0 mmol) was added and stirred for 20 minutes. The generated precipitate was removed by suction filtration, and 5 g of ice and 0.76 g (20.0 mmol) of sodium borohydride were added to the filtrate under ice cooling and stirred for 1.5 hours. 20 ml of 1N aqueous hydrogen chloride solution was added thereto, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. The oily residue thus obtained was dissolved in 36 ml of tetrahydrofuran, 0.96 g (8.04 mmol) of 3-cyanophenol, 2.30 g (8.77 mmol) of triphenylphosphine, diethyl azodicarboxylate (40% toluene solution). 50 g (8.04 mmol) was added and stirred overnight at room temperature. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 1.80 g (4.38 mmol) Yield 44%
H-NMR (CDCl3) δ 1.46 (9H, s), 2.79 (2H, d), 4.00 (1H, dd), 4.06 (1H, dd), 4.41 (1H, br), 5.13 (2H, s), 5.56 (1H, br), 7.05-7.18 (4H, m), 7.21-7.38 (5H, m)
Process 2
(3R) -3-Amino-4- (3-cyanophenoxy) butyric acid benzyl ester hydrochloride (3R) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butyric acid benzyl as a raw material, 4 The title compound was obtained by de-t-butoxycarbonyl reaction by a conventional method using dioxane containing normal hydrogen chloride.
Process 3
Synthesis of ethyl (3R) -4- (3-amidinophenoxy) -3- [4- (piperidin-4-yl) methylbenzoylamino] butyrate ditrifluoroacetate
To 334 mg (1.00 mmol) of methyl 4- [1- (t-butoxycarbonyl) piperidin-4-ylidene] methylbenzoate were added 95 mg of palladium-carbon and 20 ml of methanol, and the mixture was stirred for 15 hours in the presence of hydrogen. After Celite filtration, the solvent was evaporated and the residue obtained was added 1N sodium hydroxide 4 ml and ethanol 6 ml and stirred for 18 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the residue obtained by evaporating the solvent was dissolved in 5 ml of dichloromethane, 0.46 ml (3.27 mmol) of triethylamine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Add 209 mg (1.50 mmol) of salt, 147 mg (1.09 mmol) of 1-hydroxybenzotriazole, 306 mg (0.99 mmol) of (3R) -3-amino-4- (3-cyanophenoxy) butyric acid benzyl ester hydrochloride And stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 105 mg (0.22 mmol) Yield 22%
MS (ESI, m / z) 464 (MH +)
H-NMR (DMSO-d6) δ 1.15 (3H, t), 1.22-1.40 (2H, m), 1.62-1.74 (2H, m), 1.78-1.90 (1H, m), 2.56-2.65 (2H, m), 2.69-2.90 (4H, m), 3.16-3.31 (2H, m), 4.01-4.16 (3H, m), 4.18-4.27 (1H, m), 4.64-4.78 (1H, m), 7.27- 7.45 (6H, m), 7.78 (2H, d), 8.28 (1H, br), 8.47-8.65 (2H, m), 9.16 (4H, br), 9.29 (2H, br)
Example 53
(3R) -4- (3-Amidinophenoxy) -3- [4- (1-piperidin-4-yl) methylbenzoylamino] butyric acid Synthesis of ditrifluoroacetate
(3R) -4- (3-Amidinophenoxy) -3- [4- (1-piperidin-4-yl) methylbenzoylamino] butyric acid 30 mg (0.05 mmol) of ditrifluoroacetate as a starting material, The title compound was obtained in the same manner as in Step 51 of Example 51.
Yield 17 mg (0.22 mmol) Yield 62%
MS (ESI, m / z) 439 (MH +)
H-NMR (DMSO-d6) δ 1.26-1.45 (2H, m), 1.61-1.73 (2H, m), 1.74-1.89 (1H, m), 2.58 (2H, d), 2.67-2.85 (4H, m), 3.24-3.36 (2H, m), 4.10 (1H, dd), 4.24 (1H, dd), 4.68 (1H, ddt), 7.27 (2H, d), 7.33 (1H, d), 7.43 (2H , br), 8.28 (1H, br), 8.47-8.65 (2H, m), 9.16 (4H, br), 9.29 (2H, br)
Example 54
Synthesis of ethyl (3R) -3-[(biphenyl-4-carbonyl) amino] -4- (3-amidinophenoxy) butyrate trifluoroacetate
Process 1
Synthesis of 4-phenylbenzoyl chloride
To 1.05 g (5.3 mmol) of 4-phenylbenzoic acid was added 10 ml of thionyl chloride, and the mixture was heated to reflux for 3 hours. The solvent was distilled off to obtain a crude product.
Process 2
Synthesis of benzyl (3R) -3-[(biphenyl-4-carbonyl) amino] -4- (3-cyanophenoxy) butyrate
310 mg (1.0 mmol) of (3R) -3-amino-4- (3-cyanophenoxy) butyric acid benzyl hydrochloride was dissolved in 10 ml of dimethylformamide, and 0.18 ml (1.3 mmol) of triethylamine was added. Under ice cooling, 282 mg (1.3 mmol) of 4-phenylbenzoyl chloride was added and stirred for 30 minutes, then returned to room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give the title compound Got.
Yield 220 mg (0.45 mmol) Yield 45%
H-NMR (CDCl3) δ 2.93 (2H, dt), 4.19 (2H, dt), 4.83-4.97 (1H, m), 7.14 (2H, dd), 7.24-7.29 (2H, m), 7.33-7.51 (8H, m), 7.59-7.68 (4H, m), 7.83 (2H, d)
Process 3
Synthesis of ethyl (3R) -3-[(biphenyl-4-carbonyl) amino] -4- (3-amidinophenoxy) butyrate trifluoroacetate
Starting from 220 mg (0.45 mmol) of benzyl (3R)-[(biphenyl-4-carbonyl) amino] -4- (3-cyanophenoxy) butyrate, the title compound was prepared according to the same procedure as in Step 1 of Example 1. Obtained.
Yield 115 mg (0.21 mmol) Yield 46%
MS (ESI, m / z) 446 (MH +)
H-NMR (DMSO-d6) δ 1.16 (3H, t), 2.80 (2H, d), 4.07 (2H, q), 4.08-4.17 (1H, m), 4.20-4.29 (1H, m), 4.64 -4.68 (1H, m), 7.29-7.59 (7H, m), 7.74 (2H, d), 7.78 (2H, d), 7.93 (2H, d), 8.62 (1H, d), 9.11 (2H, br ), 9.29 (2H, br)
Example 55
Synthesis of (3R) -3-[(biphenyl-4-carbonyl) amino] -4- (3-amidinophenoxy) butyric acid trifluoroacetate
(3R) -3-[(Biphenyl-4-carbonyl) amino] -4- (3-amidinophenoxy) butyric acid ethyl trifluoroacetate (120 mg, 0.18 mmol) was dissolved in 5 ml of concentrated hydrochloric acid and stirred at 60 ° C. for 19 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and freeze-drying the fraction of interest.
Yield 14 mg (0.03 mmol) Yield 15%
MS (ESI, m / z) 418 (MH +)
H-NMR (DMSO-d6) δ 2.71 (2H, d), 4.09-4.20 (1H, m), 4.21-4.30 (1H, m), 4.63-4.75 (1H, m), 7.33-7.59 (7H, m), 7.74 (2H, d), 7.78 (2H, d), 7.95 (2H, d), 8.61 (1H, d), 9.22 (4H, br)
Example 56
Synthesis of (3R) -4- (3-amidinophenoxy) -3-[(4-dimethylcarbamoylbenzoyl) amino] butyric acid trifluoroacetate
Step 1 Synthesis of 4-dimethylcarbamoylbenzoic acid
To 30 ml of 50% dimethylamine aqueous solution, 5 g (25.2 mmol) of terephthalic acid monomethyl ester chloride was dissolved in 20 ml of dioxane and added under ice cooling. After stirring for 30 minutes, 50 ml of 1N aqueous sodium hydroxide solution was added and stirred at room temperature for 2 days. The reaction mixture was washed with ethyl acetate, acidified with hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting residue was washed with hexane and dried. A compound was obtained.
Yield 2.58 g (13.4 mmol) Yield 53%
H-NMR (CDCl3) δ2.85 (3H, br), 2.95 (3H, br), 7.50 (2H, d), 7.97 (2H, d)
Process 2
Synthesis of benzyl (3R) -4- (3-cyanophenoxy) -3-[(4-dimethylcarbamoylbenzoyl) amino] butyrate
(3R) -4 obtained by adding a 1N aqueous sodium hydroxide solution to benzyl hydrochloride of (3R) -4- (3-cyanophenoxy) -3-aminobutyric acid and treating with ethyl acetate as an extraction solvent in a conventional manner. 300 mg (0.97 mmol) of benzyl- (3-cyanophenoxy) -3-aminobutyrate, 193 mg (1 mmol) of 4-dimethylcarbamoylbenzoic acid, 192 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 1 mmol), 155 mg (1 mmol) of 1-hydroxybenzotriazole was stirred overnight at room temperature in 10 ml of dichloromethane. Add 1N hydrochloric acid to the reaction mixture and extract with dichloromethane. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was reversed-phase high-speed using octadodecyl group chemically bonded silica gel as a filler. The title compound was obtained by liquid chromatography, eluting with a mixed solvent of water and acetonitrile containing 0.1% of trifluoroacetic acid (v / v), and lyophilizing the fraction of interest.
Yield 178 mg (0.37 mmol) Yield 37%
H-NMR (DMSO-d6) δ2.82 (2H, d), 2.90 (3H, br), 3.00 (3H, br), 4.05-4.25 (2H, m), 4.70 (1H, m), 5.10 (2H , s), 7.26-7.35 (6H, m), 7.38-7.51 (5H, m), 7.84 (2H, d), 8.64 (1H, d)
Process 3
Synthesis of (3R) -4- (3-amidinophenoxy) -3-[(4-dimethylcarbamoylbenzoyl) amino] butyric acid trifluoroacetate
178 mg (0.38 mmol) of benzyl (3R) -4- (3-cyanophenoxy) -3-[(4-dimethylcarbamoylbenzoyl) amino] butyrate was stirred in 6 ml of dioxane containing 4N hydrogen chloride, and 1 ml of ethanol. After stirring at room temperature for 6 days, the solvent was distilled off under reduced pressure. The obtained residue was stirred in 10 ml of ethanol, 60 mg of ammonium carbonate was added and stirred at room temperature for 2 days, and the solvent was distilled off. Concentrated hydrochloric acid (15 ml) was added to the obtained residue, stirred at 40 ° C. overnight, the solvent was distilled off, and the resulting residue was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material. And eluted with a mixed solvent of water and acetonitrile containing 0.1% of trifluoroacetic acid (v / v), and the desired fraction was lyophilized to give the title compound.
Yield 108 mg (0.21 mmol) Yield 55%
MS (ESI, m / z) 413 (MH +)
H-NMR (DMSO-d6) δ2.80 (2H, d), 3.00 (3H, br), 3.10 (3H, br), 4.15-4.35 (2H, m), 4.75 (1H, m), 7.40-7.49 (3H, m), 7.54-7.64 (3H, m), 7.96 (2H, d), 8.70 (1H, d), 9.15 (2H, br), 9.35 (2H, br)
Example 57
Synthesis of (3R) -4- (3-amidinophenoxy) -3-[(4-guanidinobenzoyl) amino] butyric acid ditrifluoroacetate
Process 1
Synthesis of (3R) -4- (3-cyanophenoxy) -3-[(4-guanidinobenzoyl) amino] butyric acid trifluoroacetate
(3R) -4- (3-Cyanophenoxy) -3-aminobutyric acid benzyl 247 mg (0.8 mmol), 4-guanidinobenzoic acid monohydrochloride 138 mg (0.64 mmol), 1-hydroxybenzotriazole (hydrous, 87 %) 100 mg (0.64 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 123 mg (0.64 mmol) was stirred in dimethylformamide 5 ml at room temperature for 3 days, and then the solvent was distilled off under reduced pressure. Add normal aqueous sodium hydroxide and extract with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was subjected to reverse-phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, The title compound was obtained by elution with a mixed solvent of water and acetonitrile containing 0.1% of trifluoroacetic acid (v / v) and lyophilizing the fraction of interest.
Yield 123 mg (0.21 mmol) Yield 33%
H-NMR (CD3OD) δ 2.90 (2H, m), 4.20 (2H, m), 4.85 (1H, m), 5.15 (2H, s), 7.20-7.38 (10H, m), 7.41 (1H, t ), 7.82 (2H, d)
Process 2
Synthesis of (3R) -4- (3-amidinophenoxy) -3-[(4-guanidinobenzoyl) amino] butyric acid ditrifluoroacetate
(3R) -4- (3-Cyanophenoxy) -3-[(4-guanidinobenzoyl) amino] butyric acid benzyl trifluoroacetate 178 mg (0.3 mmol) was used in the same manner as in Example 56, step 3 to obtain the title. A compound was obtained.
Yield 111 mg (0.18 mmol) Yield 60%
MS (ESI, m / z) 399 (MH +)
H-NMR (DMSO-d6) δ 2.75 (2H, d), 4.05-4.25 (2H, m), 4.70 (1H, m), 7.30-7.43 (5H, m), 7.53 (1H, t), 7.68 (4H, s), 7.92 (2H, d), 8.58 (1H, d), 9.13 (2H, s), 9.30 (2H, s), 10.13 (1H, s)
Example 58
Synthesis of (3R) -4- (3-amidinophenoxy) -3- [4- (pyrrolidin-1-yl) benzoylamino] butyric acid trifluoroacetate
505 mg (1.23 mmol) of benzyl (3R) -3- (t-butoxycarbonyl) amino-4- (3-cyanophenoxy) butyrate was dissolved in 5 ml of 4N dioxane hydrochloride and 2.5 ml of dioxane and stirred for 15 hours. . After evaporation of the solvent, the residue was dissolved in 10 ml of dichloromethane, 334 mg (1.00 mmol) of 4- (pyrrolidin-1-yl) benzoic acid, 0.86 ml (6.15 mmol) of triethylamine, 1- (3-dimethylaminopropyl) 258 mg (1.35 mmol) of -3-ethylcarbodiimide hydrochloride and 183 mg (1.35 mmol) of 1-hydroxybenzotriazole were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was added with 4N dioxane hydrochloride (5 ml) and ethanol (1 ml) for 96 hours. Stir. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 10 ml of an ethanol solution containing 10% ammonia (w / v) and stirred for 24 hours. The solvent was distilled off under reduced pressure, 5 ml of concentrated hydrochloric acid was added to the resulting residue, and the mixture was stirred at 50 ° C. for 15 hours. The residue obtained by distilling off the solvent under reduced pressure was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 170 mg (0.32 mmol) Yield 24%
MS (ESI, m / z) 411 (MH +)
H-NMR (DMSO-d6) δ 1.87-2.03 (4H, m), 2.70 (2H, d), 3.20-3.35 (4H, m), 4.04 (1H, dd), 4.21 (1H, dd), 4.63 (1H, ddt), 6.53 (2H, d), 7.32-7.45 (3H, m), 7.53 (1H, dd), 7.72 (2H, d), 8.11 (1H, d), 9.06 (2H, br), 9.27 (2H, br)
Example 59
Synthesis of ethyl (3R) -4- (3-amidinophenoxy) -3- [4- (pyrrolidin-1-yl) benzoylamino] butyrate trifluoroacetate
Synthesis of benzyl (3R) -4- (3-cyanophenoxy) -3- [4- (pyrrolidin-1-yl) benzoylamino] butyrate
5.1 g (12.4 mmol) of benzyl (3R) -3- (t-butoxycarbonyl) amino-4- (3-cyanophenoxy) butyrate was dissolved in 20 ml of 4N dioxane hydrochloride and 10 ml of dioxane and stirred for 15 hours. . After evaporating the solvent, the residue was dissolved in 10 ml of dichloromethane, 2.61 g (13.7 mmol) of 4- (pyrrolidin-1-yl) benzoic acid, 8.63 ml (62 mmol) of triethylamine, 1- (3-dimethylaminopropyl) ) -3-ethylcarbodiimide hydrochloride 2.61 g (13.7 mmol) and 1-hydroxybenzotriazole 1.85 mg (13.7 mmol) were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by the same procedure as in Example 1, step 6, followed by the title compound. Got.
Yield 800 mg (1.45 mmol) Yield 28%
MS (ESI, m / z) 439 (MH +)
H-NMR (DMSO-d6) δ 1.14 (3H, t), 1.86-2.01 (4H, m), 2.70 (2H, d), 3.18-3.33 (4H, m), 4.02 (1H, dd), 4.10 (1H, q), 4.21 (1H, dd), 4.63 (1H, ddt), 6.53 (2H, d), 7.35-7.51 (3H, m), 7.53 (1H, dd), 7.72 (2H, d), 8.11 (1H, d), 9.04 (2H, br), 9.28 (2H, br)
Example 60
Synthesis of (3R) -3- (4-carbamoylbenzoylamino) -4- (3-amidinophenoxy) butyric acid ditrifluoroacetate
Process 1
Synthesis of benzyl (3R) -3- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butyrate
1.8 g (4.38 mmol) of benzyl (3R) -3-tert-butoxycarbonylamino-4- (3-cyanophenoxy) butyrate is dissolved in 20 ml of 4N hydrogen chloride in dioxane and stirred at 0 ° C. for 6 hours. did. The oily residue obtained by distilling off the solvent was dissolved in 5 ml of dichloromethane, and 1.09 g (6.58 mmol) of 4-cyanobenzoic acid chloride and 1.22 ml (8.76 mmol) of triethylamine were added under ice-cooling. Stir overnight. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 1.21 g (2.75 mmol) Yield 63%
H-NMR (CDCl3) δ 2.86 (1H, dd), 2.95 (1H, dd), 4.12 (1H, dd), 4.20 (1H, dd), 4.85 (1H, br), 5.16 (2H, s), 7.09 (1H, d), 7.11 (1H, dd), 7.24-7.40 (7H, m), 7.72 (2H, d), 7.83 (2H, d)
Process 2
Synthesis of (3R) -3- (4-carbamoylbenzoylamino) -4- (3-amidinophenoxy) butyric acid ditrifluoroacetate
(3R) -3- (4-Cyanobenzoylamino) -4- (3-cyanophenoxy) butyric acid benzyl was added to (w / v) ethanol containing 30% hydrogen chloride and stirred overnight at room temperature. Subsequently, the mixture was dissolved in an ethanol solution containing 10% ammonia (w / v) at room temperature and stirred at room temperature overnight. The residue obtained by distilling off the solvent was dissolved in concentrated hydrochloric acid and stirred at 40 ° C. for 6 hours. The residue obtained by distilling off hydrogen chloride was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
MS (ESI, m / z) 385 (MH +)
H-NMR (DMSO-d6) δ 2.75 (2H, d), 4.12 (1H, dd), 4.23 (1H, dd), 4.68 (1H, br), 7.35 (1H, d), 7.40 (1H, d ), 7.42 (1H, s), 7.53 (1H, t), 7.89 (2H, d), 7.96 (2H, d), 8.09 (2H, br), 8.66 (1H, d), 9.24 (2H, br) , 9.29 (2H, br)
Example 61
(3R) -4- (3-amidinophenoxy) -3-[(4-dimethylamino) benzoylamino] butyric acid ethyl trifluoroacetate and
Synthesis of (3R) -4- (3-amidinophenoxy) -3-[(4-dimethylamino) benzoylamino] butyric acid trifluoroacetate
700 mg (1.70 mmol) of benzyl (3R) -3- (t-butoxycarbonyl) amino-4- (3-cyanophenoxy) butyrate was dissolved in 5 ml of 4N dioxane hydrochloride and 2.5 ml of dioxane and stirred for 15 hours. . After evaporating the solvent, the residue was dissolved in 10 ml of dichloromethane, 282 mg (1.71 mmol) of 4-dimethylaminobenzoic acid, 1.19 ml (8.55 mmol) of triethylamine, 1- (3-dimethylaminopropyl) -3-ethyl. Carbodiimide hydrochloride 748 mg (1.88 mmol) and 1-hydroxybenzotriazole 254 mg (1.88 mmol) were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue obtained was obtained by subjecting the residue to the procedure of Example 56, step 3. Got. However, ethanol containing 10% ammonia was used in place of ammonium carbonate in ethanol.
(3R) -4- (3-Amidinophenoxy) -3- (4-dimethylaminobenzoylamino] butyric acid ethyl trifluoroacetate
Yield 10 mg (0.02 mmol) Yield 1%
MS (ESI, m / z) 413 (MH +)
H-NMR (DMSO-d6) δ 1.14 (3H, t), 2.78 (2H, d), 2.97 (6H, s), 4.06 (2H, q), 4.10 (2H, dd), 4.23 (2H, dd ), 4.68 (2H, dd), 6.69 (2H, d), 7.30-7.42 (3H, m), 7.53 (1H, dd), 7.71 (2H, d), 8.18 (2H, d), 9.10 (2H, br), 9.28 (2H, br)
(3R) -4- (3-Amidinophenoxy) -3- (4-dimethylaminobenzoylamino] butyric acid trifluoroacetate
Yield 70 mg (0.14 mmol) Yield 8%
MS (ESI, m / z) 385 (MH +)
H-NMR (DMSO-d6) δ 2.69 (2H, d), 2.97 (6H, s), 4.04 (2H, dd), 4.22 (2H, dd), 4.64 (2H, q), 6.70 (2H, d ), 7.33-7.44 (3H, m), 7.53 (1H, dd), 7.72 (2H, d), 8.14 (2H, d), 9.09 (2H, br), 9.25 (2H, br)
Example 62
(3R) -4- (3-Amidinophenoxy) -3- [4- (1-acetimidoyl-4-piperidyloxy) benzoylamino] butyric acid Synthesis of ditrifluoroacetate
Process 1
Synthesis of ethyl 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoate
1.76 g (9.3 mmol) of 1-t-butoxycarbonyl-4-hydroxypiperidine obtained by t-butoxycarbonylation of 4-hydroxypiperidine with di-t-butyldicarbonate by a conventional method; 1.7 g (10.2 mmol) of ethyl benzoate and 2.44 g (9.3 mmol) of triphenylphosphine were dissolved in 40 ml of tetrahydrofuran, and 1.62 g (9.3 mmol) of diethyl azodicarboxylate was added at room temperature and stirred overnight. . The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.57 g (4.5 mmol) Yield 44%
H-NMR (CDCl3) δ 1.38 (3H, t), 1.50 (9H, s) 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 3.30-3.41 (2H, m), 3.63- 3.75 (2H, m), 4.35 (2H, q), 4.55 (1H, m), 6.90 (2H, d), 8.00 (2H, d)
Process 2
Synthesis of 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoic acid
847 mg (2.43 mmol) of ethyl (1-t-butoxycarbonyl-4-piperidyloxy) benzoate was dissolved in 50 ml of ethanol, 5 ml of 1N sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated and treated according to a conventional method using ethyl acetate as an extraction solvent to obtain the title compound.
Yield 697 mg (2.2 mmol) Yield 92%
H-NMR (CDCl3) δ1.50 (9H, s), 1.70-2.00 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.60 (1H, s), 6.95 (2H, d), 8.05 (2H, d)
Process 3
Synthesis of benzyl (3R) -4- (3-cyanophenoxy) -3- [4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoylamino] butyrate
1.46 g (3.56 mmol) of benzyl (3R) -3- (t-butoxycarbonyl) amino-4- (3-cyanophenoxy) butyrate was dissolved in 10 ml of 4N dioxane hydrochloride and 5 ml of dioxane and stirred for 15 hours. . After evaporation of the solvent, the residue was dissolved in 20 ml of dichloromethane, and 1.14 g (3.56 mmol) 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoic acid 2.48 ml (17.8 mmol) triethylamine, 748 mg (3.92 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 529 mg (3.92 mmol) of 1-hydroxybenzotriazole were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the title compound. It was.
Yield 1.0 g (1.63 mmol) Yield 46%
H-NMR (CDCl3) δ 1.45 (9H, s), 1.68-1.81 (2H, m), 1.84-1.97 (2H, m), 2.88 (2H, dt), 3.27-3.40 (2H, m), 3.61 -3.73 (2H, m), 4.04-4.23 (2H, m), 4.46-4.58 (1H, m), 4.77-4.90 (1H, m), 5.13 (2H, s), 6.89 (2H, d), 7.02 -7.13 (3H, m) ,. 7.27-7.37 (6H, m), 7.68 (2H, d)
Process 4
Synthesis of (3R) -4- (3-amidinophenoxy) -3- [4- (1-acetimidoyl-4-piperidyloxy) benzoylamino] butyric acid trifluoroacetate
(3R) -4- (3-Cyanophenoxy) -3- [4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoylamino] benzyl butyl (1.0 g, 1.63 mmol) was added to 4N dioxane hydrochloride. 10 ml and 2 ml of ethanol were added and stirred for 48 hours. After the solvent was distilled off, it was dissolved in 10 ml of ethanol solution containing 10% ammonia (w / v) and stirred for 24 hours. After distilling off the solvent, the residue was dissolved in 10 ml of ethanol, 1.0 g (8.16 mmol) of ethylacetoimidate hydrochloride and 1.1 ml (8.16 mmol) of triethylamine were added, and the mixture was stirred for 24 hours. After the solvent was distilled off, the residue was dissolved in 10 ml of concentrated hydrochloric acid and stirred at 40 ° C. for 18 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 600 mg (0.85 mmol) Yield 52%
MS (ESI, m / z) 482 (MH +)
H-NMR (DMSO-d6) δ 1.66-1.85 (2H, m), 2.02-2.16 (2H, m), 2.29 (3H, s), 2.71 (2H, d), 3.43-3.56 (3H, m) , 4.00-4.13 (2H, m), 4.18-4.30 (2H, m), 4.58-4.63 (2H, m), 4.76-4.86 (1H, m), 7.07 (2H, d), 7.32-7.50 (3H, m), 7.54 (1H, dd), 7.84 (2H, d), 8.39 (1H, d), 8.60 (1H, br), 9.09 (2H, br), 9.14 (1H, br), 9.28 (2H, br )
Example 63
Synthesis of 3- [5- (4-amidinophenyl) -5-oxopentyl] oxybenzamidine ditrifluoroacetate
Process 1
Synthesis of 4- (5-chloro-1-oxopentyl) benzonitrile
4-acetylbenzonitrile (1 g, 6.9 mmol) was dissolved in tetrahydrofuran (8 ml), and lithium bistrimethylsilylamide (1M hexane solution) (9 ml) was gradually added at -70 ° C and stirred for 30 minutes. 1.43 g (7 mmol) of 1-chloro-3-iodopropane dissolved in 6 ml of tetrahydrofuran was added and stirred overnight at room temperature. The reaction mixture was poured into water, extracted with ethyl acetate, washed with 1N hydrochloric acid and saturated brine, and dried over powdered magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography to give the title compound.
Yield 59.3 mg (0.27 mmol) Yield 3.9%
H-NMR (CDCl3) δ1.82-1.95 (4H, m), 3.03 (2H, t), 3.60 (2H, t), 7.80 (2H, d), 8.05 (2H, d)
Process 2
Synthesis of 3- [5- (4-cyanophenyl) -5-oxopentyl] oxybenzonitrile 53 mg (0.24 mmol) of 4- (5-chloro-1-oxopentyl) benzonitrile was dissolved in 2 ml of dimethylformamide. , 33 mg (0.24 mmol) of potassium carbonate, 40 mg of potassium iodide, and 29 mg (0.24 mmol) of 3-hydroxybenzonitrile were added and stirred at 70 ° C. overnight. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate, washed with 1N sodium hydroxide and saturated brine, dried over powdered magnesium sulfate, and the solvent was evaporated. Silica gel chromatography gave the title compound.
Yield 24 mg (0.079 mmol) Yield 33%
H-NMR (CDCl3) δ1.82-2.00 (4H, m), 3.08 (2H, t), 4.02 (2H, t), 7.12 (1H, d), 7.14 (1H, s), 7.22 (1H, d ), 7.37 (1H, t), 7.79 (2H, d), 8.03 (2H, d)
Process 3
Synthesis of 3- [5- (4-amidinophenyl) -5-oxopentyl] oxybenzamidine ditrifluoroacetate
The title compound was obtained in the same manner as in Step 1 of Example 1 using 43 mg (0.14 mmol) of 3- [5- (4-cyanophenyl) -5-oxopentyl] oxybenzonitrile as a starting material. Yield 8.8 mg (0.015 mmol) Yield 11%
MS (ESI, m / z) 339 (MH +)
H-NMR (DMSO-d6) δ 1.78-1.90 (4H, m), 3.20 (2H, t), 4.12 (2H, t), 7.30 (1H, d), 7.37 (1H, s), 7.39 (1H , d), 7.53 (1H, t), 7.94 (2H, d), 8.16 (2H, d), 9.24-9.48 (8H, brm)
Example 64
Synthesis of 4- [4- (3-amidinophenoxy) butyryl] -N, N-dimethylbenzamide trifluoroacetate
Process 1
Synthesis of 2- (4-bromophenyl) -2- (3-chloropropyl) -5,5-dimethyl-1,3-dioxane
4'-bromo-4-chlorobutyrophenone 10 g (38.2 mmol), 2,2-dimethyl-1,3-propanediol 4 g (38.2 mmol), p-toluenesulfonic acid monohydrate 200 mg (1 mmol) Dehydration was carried out azeotropically by heating and refluxing for 3 days. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound.
Yield 13.3 g (38 mmol) Yield 100%
H-NMR (CDCl3) δ0.60 (3H, s), 1.22 (3H, s), 1.78-2.00 (4H, m), 3.40 (4H, s), 3.50 (1H, t), 7.25 (2H, d ), 7.55 (2H, d)
Process 2
Synthesis of 3- [3- [2- (4-bromophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] propoxy] benzonitrile
236 mg (5.9 mmol) of sodium hydride (oily, 60%) was stirred in dimethylformamide, and 691 mg (5.8 mmol) of 3-hydroxybenzonitrile was added under ice cooling. After stirring at room temperature for 30 minutes, 2- (4-bromophenyl) -2- (3-chloropropyl) -5,5-dimethyl-1,3-dioxane (2 g, 5.75 mmol) was dissolved in dimethylformamide and added. And stirred at 100 ° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude product of the title compound. Yield 2.25 g (5.23 mmol) Yield 91%
H-NMR (CDCl3) δ0.60 (3H, s), 1.22 (3H, s), 1.80-2.00 (4H, m), 3.40 (4H, s), 3.93 (1H, s), 7.06 (1H, d ), 7.08 (1H, s), 7.19 (1H, d), 7.26-7.35 (3H, m), 7.52 (2H, d)
Process 3
Synthesis of 4- [4- (3-cyanophenoxy) butyryl] benzoic acid
3- [3- [2- (4-Bromophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] propoxy] benzonitrile 500 mg (1.16 mmol), tributylamine 260 mg (1.4 mmol) , 42 mg (0.06 mmol) of bis (triphenylphosphine) palladium (II) chloride was stirred overnight at 100 ° C. in a carbon monoxide atmosphere in 3 ml of 1-butanol and 5 ml of dimethylformamide. Ether was added to the reaction mixture, which was washed with water, washed with 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. To the residue were added 9 ml of 6N hydrochloric acid and 9 ml of acetic acid, and the mixture was refluxed with heating for 4 hours. The solvent was distilled off, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give a crude title compound. Yield 247 mg (0.80 mmol) Yield 69%
H-NMR (DMSO-d6) δ 2.10 (2H, m), 3.25 (2H, t), 4.10 (2H, t), 7.28 (1H, d), 7.36-7.52 (3H, m), 8.07 (4H , s)
Process 4
Synthesis of 4- [4- (3-cyanophenoxy) butyryl] -N, N-dimethylbenzamide 4- [4- (3-cyanophenoxy) butyryl] benzoic acid 240 mg (0.78 mmol), 1- (3-dimethyl Aminopropyl) -3-ethylcarbodiimide hydrochloride 150 mg (0.78 mmol), 1-hydroxybenzotriazole (hydrous, 87%) 121 mg (0.78 mmol), 50% aqueous dimethylamine solution 100 mg were mixed in 5 ml of dimethylformamide at room temperature. Stir overnight. 1N Hydrochloric acid was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography using ethyl acetate as an elution solvent to give the title compound.
Yield 149 mg (0.44 mmol) Yield 57%
H-NMR (CDCl3) δ 2.25 (2H, m), 2.98 (3H, s), 3.18 (3H, s), 3.20 (2H, t), 4.10 (2H, t), 7.12 (1H, d), 7.14 (1H, s), 7.23 (1H, d), 7.36 (1H, t), 7.51 (2H, d), 8.02 (2H, d)
Process 5
Synthesis of 4- [4- (3-amidinophenoxy) butyryl] -N, N-dimethylbenzamide trifluoroacetate
The title compound was obtained in the same manner as in Step 3 of Example 3 using 70 mg (0.21 mmol) of 4- [4- (3-cyanophenoxy) butyryl] -N, N-dimethylbenzamide.
Yield 42 mg (0.09 mmol) Yield 43%
MS (ESI, m / z) 354 (MH +)
H-NMR (DMSO-d6) δ 2.15 (2H, m), 2.83 (3H, s), 3.00 (3H, s), 3.25 (2H, t), 4.17 (2H, t), 7.30 (1H, d ), 7.38 (1H, s), 7.40 (1H, d), 7.50-7.58 (3H, m), 8.04 (2H, d), 9.30 (2H, br), 9.40 (2H, br)
Example 65
Synthesis of 4- [4- (3-amidinophenoxy) butyryl] -N, N-dimethylbenzamidine ditrifluoroacetate
70 mg (0.21 mmol) of 4- [4- (3-cyanophenoxy) butyryl] -N, N-dimethylbenzamide was stirred in dichloromethane, and 67 mg (0.45 mmol) of trimethyloxonium tetrafluoroborate was added thereto at room temperature. Stir for 2 days. After adding ethanol and distilling off dichloromethane, 71 mg of ammonium carbonate was added and stirred at room temperature for 4 days. The solvent was distilled off, dichloromethane was added, and the mixture was extracted with 1N hydrochloric acid. The aqueous layer was made alkaline by adding 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The title compound was obtained in the same manner as in Example 3, Step 3 using the residue. Yield 8 mg (0.014 mmol) Yield 7%
MS (ESI, m / z) 353 (MH +)
H-NMR (DMSO-d6) δ 2.15 (2H, m), 3.00 (3H, s), 3.22 (3H, s), 3.30 (2H, t), 4.20 (2H, t), 7.29 (1H, d ), 7.37 (1H, s), 7.38 (1H, d), 7.54 (1H, t), 7.76 (2H, d), 8.18 (2H, d), 9.03-9.42 (6H, m)
Example 66
4- [4- (3-Amidinophenoxy) butyryl] benzamidine Synthesis of ditrifluoroacetate
Process 1
Synthesis of 4- [4- (3-cyanophenoxy) butyryl] benzonitrile
3- [3- [2- (4-Bromophenyl) -5,5-dimethyl-1,3-dioxan-2-yl] propoxy] benzonitrile 500 mg (1.16 mmol), copper (I) cyanide 114 mg ( 1.27 mmol) was stirred in 1 ml dimethylformamide at 140 ° C. overnight. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. To the residue, 10 ml of ethanol and 2 ml of 6N hydrochloric acid were added and heated to reflux for 5 hours. The solvent was distilled off, 1N hydrochloric acid was added, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography using ethyl acetate-hexane as an elution solvent to obtain the title compound.
Yield 50 mg (0.17 mmol) Yield 15%
H-NMR (CDCl3) δ 2.28 (2H, m), 3.20 (2H, t), 4.10 (2H, t), 7.12 (1H, d), 7.13 (1H, s), 7.24 (1H, d), 7.36 (1H, t), 7.78 (2H, d), 8.07 (2H, d)
Process 2
4- [4- (3-Amidinophenoxy) butyryl] benzamidine Synthesis of ditrifluoroacetate salt Example 3 Step 3 using 50 mg (0.17 mmol) of 4- [4- (3-cyanophenoxy) butyryl] benzonitrile To give the title compound.
Yield 35 mg (0.06 mmol) Yield 35%
MS (ESI, m / z) 353 (MH +)
H-NMR (DMSO-d6) δ 2.15 (2H, m), 3.30 (2H, t), 4.20 (2H, t), 7.30 (1H, d), 7.37 (1H, s), 7.38 (1H, d ), 7.54 (1H, t), 7.95 (2H, d), 8.17 (2H, d), 9.18-9.50 (8H, m)
Example 67
4- (3-Amidinophenoxy) -N- (4-amidinophenyl) butyramide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 4- (3-cyanophenoxy) -2-butenoic acid ethyl ester
1 g (3.9 mmol) of ethyl 4-bromocrotonate (75%), 465 mg (3.9 mmol) of 3-hydroxybenzonitrile, 539 mg (3.9 mmol) of potassium carbonate, 647 mg (3.9 mmol) of potassium iodide, Stir in N-dimethylformamide at room temperature for 3 days. 1N Hydrochloric acid was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound.
Yield 832 mg (3.6 mmol) Yield 93%
H-NMR (CDCl3) δ1.30 (3H, t), 4.20 (2H, q), 4.75 (2H, m), 6.17 (1H, dt), 7.05 (1H, dt), 7.12-7.18 (2H, m ), 7.28 (1H, d), 7.40 (1H, t)
Process 2
Synthesis of 4- (3-cyanophenoxy) butyric acid
4- (3-Cyanophenoxy) -2-butenoic acid ethyl ester (830 mg, 3.6 mmol) and 1N aqueous sodium hydroxide solution (10 ml) were stirred in ethanol (50 ml) for 6 hours. The reaction mixture was concentrated, 1N hydrochloric acid was added, and the resulting precipitate was collected by filtration. 20 ml of ethanol and 30 mg of 10% palladium carbon were added to the filtered product, and the mixture was stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. 1N hydrochloric acid was added to the resulting residue, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound. .
Yield 290 mg (1.4 mmol) Yield 39%
H-NMR (CDCl3) δ2.15 (2H, m), 2.60 (2H, t), 4.03 (2H, t), 7.09-7.14 (2H, m), 7.24 (2H, d), 7.36 (1H, t )
Process 3
Synthesis of 4- (3-cyanophenoxy) -N- (4-cyanophenyl) butyramide
4- (3-Cyanophenoxy) butyric acid 100 mg (0.49 mmol) and triethylamine 50 mg (0.49 mmol) were stirred in dimethylformamide under ice-cooling, and ethyl chloroformate 53 mg (0.49 mmol) was added thereto. After stirring for 2 minutes, 58 mg (0.49 mmol) of p-aminobenzonitrile was added, and the mixture was warmed to room temperature and stirred overnight. 1N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound as a crude product.
Yield 113 mg (0.37 mmol) Yield 76%
H-NMR (CDCl3) δ 2.20 (2H, m), 2.60 (2H, t), 4.05 (2H, t), 7.08-7.14 (2H, m), 7.24 (2H, d), 7.36 (2H, t ), 7.49 (1H, br), 7.58-7.68 (4H, m)
Process 4
4- (3-Amidinophenoxy) -N- (4-amidinophenyl) butyramide Synthesis of ditrifluoroacetate
The title compound was obtained in the same manner as in Step 3 of Example 3 using 110 mg (0.36 mmol) of 4- (3-cyanophenoxy) -N- (4-cyanophenyl) butyramide.
Yield 5.2 mg (0.009 mmol) Yield 3%
MS (ESI, m / z) 340 (MH +)
H-NMR (DMSO-d6) δ 2.10 (2H, m), 2.60 (2H, t), 4.15 (2H, t), 7.30 (1H, d), 7.37 (1H, s), 7.39 (1H, d ), 7.53 (1H, t), 7.80 (4H, s), 9.00-9.30 (8H, m), 10.45 (1H, s)
Example 68
Synthesis of 3- (3-amidinophenoxy) -N- (4-amidinophenyl) propionamide ditrifluoroacetate
Process 1
3- (3-Cyanophenoxy) propionic acid methyl ester
Sodium hydride (24 mg, 0.6 mmol) was stirred in acrylic acid methyl ester (10 ml), and 3-hydroxybenzonitrile (1 g, 8.4 mmol) and hydroquinone (2 mg) were added. After heating and refluxing for 3 days, acetic acid was added and concentrated under reduced pressure. Ethyl acetate was added and the mixture was washed with water, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound. Yield 996 mg (4.85 mmol) Yield 58%
H-NMR (CDCl3) δ 2.80 (2H, t), 3.77 (3H, s), 4.25 (2H, t), 7.14 (1H, d), 7.15 (1H, s), 7.26 (1H, d), 7.37 (1H, t),
Process 2
Synthesis of 3- (3-cyanophenoxy) propionic acid
500 mg (2.4 mmol) of 3- (3-cyanophenoxy) propionic acid methyl ester was heated in 70 ml of 6N hydrochloric acid at 70 ° C. for 30 minutes. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the title compound.
Yield 476 mg (2.5 mmol) Yield 100%
H-NMR (DMSO-d6) δ 2.70 (2H, t), 4.23 (2H, t), 7.29 (1H, d), 7.38-7.48 (2H, m), 7.49 (1H, t)
Process 3
Synthesis of 3- (3-cyanophenoxy) -N- (4-cyanophenyl) propionamide
3- (3-Cyanophenoxy) propionic acid 122 mg (0.64 mmol), N-methylmorpholine 150 mg (1.5 mmol), ethyl chloroformate 70 mg (0.64 mmol), 4-aminobenzonitrile 82 mg (0.7 mmol) ) To give a crude title compound in the same manner as in Example 67, Step 3. This was purified by silica gel chromatography using ethyl acetate-hexane as an elution solvent.
Yield 36 mg (0.12 mmol) Yield 19%
H-NMR (CD3OD) δ2.90 (2H, t), 4.40 (2H, t), 7.23-7.31 (3H, m), 7.44 (1H, t), 7.65-7.83 (4H, m)
Process 4
Synthesis of 3- (3-amidinophenoxy) -N- (4-amidinophenyl) propionamide ditrifluoroacetate
The title compound was obtained in the same manner as in Step 3 of Example 3 using 35 mg (0.12 mmol) of (3-cyanophenoxy) -N- (4-cyanophenyl) propionamide.
Yield 8.4 mg (0.015 mmol) Yield 13%
MS (ESI, m / z) 326 (MH +)
H-NMR (DMSO-d6) δ2.90 (2H, t), 4.40 (2H, t), 7.32 (1H, d), 7.37-7.42 (2H, m), 7.54 (1H, t), 7.82 (4H , s), 9.00 (2H, br), 9.20 (4H, br), 9.30 (2H, br), 10.60 (1H, s)
Example 69
N- [3- (3-Amidinophenoxymethyl)] phenyl-4-amidinobenzamide Synthesis of ditrifluoroacetate
Synthesis of
Process 1
Synthesis of 3- (3-nitrobenzyloxy) benzonitrile
1.70 g (10.0 mmol) of 3-nitrobenzyl chloride, 1.48 g (12.4 mmol) of 3-cyanophenol and 3.58 g (25.9 mmol) of potassium carbonate are suspended in 80 ml of dimethylformamide and stirred at 95 ° C. overnight. did. After standing to cool, 150 ml of water was added and the precipitated solid was filtered. The solid was further washed with 100 ml water followed by 20 ml ethyl acetate. The title compound was obtained by drying under reduced pressure.
Yield 2.32 g (9.12 mmol) Yield 91.2%
H-NMR (DMSO-d6) δ5.38 (2H, s), 7.38-7.42 (2H, m), 7.48-7.59 (2H, m), 7.75 (1H, dd), 7.93 (1H, dd), 8.23 (1H, dd), 8.35 (1H, d)
Process 2
Synthesis of 3- [3-aminobenzyloxy] benzonitrile
2.32 g (9.12 mmol) of 3- [3-nitrobenzyloxy] benzonitrile and 4.38 g of zinc were suspended in 50 ml of acetic acid and stirred at 45 ° C. for 4 hours. The insoluble material was filtered off, the filtrate was evaporated, 100 ml of chloroform and 50 ml of 1N aqueous sodium hydroxide solution were added to separate the solution, and then treated according to a conventional method to obtain the title compound.
Yield 1.42 g (6.33 mmol) Yield 69.4%
H-NMR (DMSO-d6) δ5.03 (2H, s), 5.09 (2H, brs), 6.50 (1H, dd), 6.55 (1H, d), 6.63 (1H, d), 7.02 (1H, dd ), 7.35 (1H, dd), 7.40 (1H, dd), 7.42 (1H, d), 7.43 (1H, dd)
Process 3
N- [3- (3-Amidinophenoxymethyl) phenyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Condensation was carried out in the same manner as in Step 4 of Example 4 using 2.48 g (11.1 mmol) of 3- [3-aminobenzyloxy] benzonitrile and 1.18 g (8.02 mmol) of 4-cyanobenzoic acid. After obtaining 3- (3-cyanophenoxymethyl)] phenyl-4-cyanobenzamide, the title compound was obtained in the same manner as in Step 1 of Example 1 without purification.
Yield 895 mg (1.45 mmol) Yield 18.1%
MS (ESI, m / z) 388 (MH +)
H-NMR (DMSO-d6) δ5.24 (2H, s), 7.22 (1H, d), 7.25-7.32 (6H, m), 7.78 (1H, d), 8.00 (2H, d), 8.20 (2H , d), 9.38 (2H, s), 9.45 (2H, s), 9.62 (2H, s), 9.80 (2H, s), 10.60 (1H, s)
Example 70
N-[(1R) -1- (2-methylpropyl) -2- (3-amidinophenoxy) ethyl] -4- (pyrrolidin-1-yl) benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of [(1R) -2-chloro-1- (2-methylpropyl) ethyl] t-butyl carbamate Using 5 g (21.6 mmol) of Nt-butoxycarbonyl-D-leucine, ethyl chloroformate 44 g (22.5 mol), 3.21 g (24.8 mmol) of diisopropylethylamine were converted to the corresponding mixed acid anhydride in 50 ml of THF, and then reduced with 2.12 g of sodium borohydride (1R)- A crude product of t-butyl 2-hydroxy-1- (2-methylpropyl) ethylcarbamate was obtained.
H-NMR (CDCl3) δ0.92 (3H, d), 0.94 (3H, d), 1.27-1.38 (2H, m), 1.42 (9H, s), 1.60-1.73 (1H, m), 2.68-4.18 (3H, m), 4.67 (1H, d)
The crude product of t-butyl (1R) -2-hydroxy-1- (2-methylpropyl) ethylcarbamate was added with 2.47 g (21.6 mmol) of methanesulfonyl chloride and 4.52 g (35.0 mmol) of diisopropylethylamine. The title compound was obtained by reacting according to a conventional method to obtain a mesyl compound and reacting with 2.15 g (50.7 mol) of lithium chloride in 120 ml of dimethylformamide.
Yield 2.35 g (9.97 mmol) Yield 46.2%
H-NMR (CDCl3) δ0.92 (3H, d), 0.94 (3H, d), 1.27-1.38 (2H, m), 1.42 (9H, s), 1.58-1.73 (1H, m), 2.88-4.18 (3H, m), 4.75 (1H, d)
Process 2
Synthesis of t-butyl (1R) -2- (3-cyanophenoxy) -1- (2-methylpropyl) ethylcarbamate
2.35 g (9.97 mmol) of t-butyl (1R) -2-chloro-1- (2-methylpropyl) ethylcarbamate, 2.42 g (20.3 mmol) of 3-cyanophenol and 2.72 g of potassium carbonate ( 19.7 mmol) was reacted in dimethylformamide and treated according to a conventional method to obtain the title compound.
Yield 1.27 g (3.99 mmol) Yield 40.0%
H-NMR (CDCl3) δ0.91 (3H, d), 0.94 (3H, d), 1.42 (9H, s), 1.40-1.78 (3H, m), 3.88-4.09 (3H, m), 4.59-4.67 (1H, m), 7.10-7.42 (4H, m)
Process 3
N-[(1R) -2- (3-amidinophenoxy) -1- (2-methylpropyl) ethyl] -4- (pyrrolidin-1-yl) benzamide Synthesis of ditrifluoroacetate
The title compound was obtained in the same manner as in Example 59 using 1.27 g (3.99 mmol) of t-butyl (1R) -2- (3-cyanophenoxy) -1- (2-methylpropyl) ethylcarbamate. It was.
Yield 170 mg (0.325 mmol) Yield 8.15%
H-NMR (DMSO-d6) δ0.88 (3H, d), 0.91 (3H, d), 1.41-1.78 (3H, m), 1.82-2.01 (4H, m), 3.15-3.30 (4H, m) , 3.95 (1H, dd), 4.10 (1H, dd), 4.32-4.42 (1H, d), 6.55 (2H, d), 7.35 (1H, d), 7.38 (1H, dd), 7.40 (1H, d ), 7.53 (1H, dd), 7.65 (1H, dd), 7.93 (1H, d), 9.21 (2H, s), 9.27 (2H, s)
Example 71
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid monoethyl ditrifluoroacetate and
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid diethyl ditrifluoroacetate
Process 1
Synthesis of benzyl 4-hydroxypiperidine-1-carboxylate
2-Hydroxypiperidine (25.0 g, 247 mmol) was dissolved in dichloromethane (800 ml), and benzyloxycarbonyl chloride (38 ml, 266 mmol) and triethylamine (75 ml, 538 mmol) were added at 0 ° C., followed by stirring at room temperature for 15 hours. Treatment was performed according to a conventional method using dichloromethane as an extraction solvent to obtain an oily residue. This was used in the next reaction without purification.
Yield 44.6 g (203 mmol) Yield 82%
Process 2
Synthesis of methyl (2S) -2- (t-butoxycarbonylamino) -3- (4-hydroxyphenyl) propionate
L-tyrosine methyl ester hydrochloride 15.2 g (65.6 mmol) is dissolved in 200 ml of dichloromethane, and 20 ml (143 mmol) of triethylamine and 13.1 g (60.0 mmol) of di-t-butyl dicarbonate are dissolved in 50 ml of dichloromethane at room temperature. Was added and stirred for 15 hours. Treatment was performed according to a conventional method using dichloromethane as an extraction solvent to obtain an oily residue. This was used in the next reaction without purification.
Yield 19.2 g (65.2 mmol) Yield 99%
Process 3
Synthesis of methyl (2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propionate
18.9 g (86.2 mmol) of benzyl 4-hydroxypiperidine-1-carboxylate, 25.4 g of methyl (2S) -2- (t-butoxycarbonylamino) -3- (4-hydroxyphenyl) propionate (86. 2 mmol) and 27.1 g (103.4 mmol) of triphenylphosphine were dissolved in 500 ml of tetrahydrofuran, and 37.5 g (86.2 mmol) of diethyl azodicarboxylate was added at room temperature, followed by stirring for 15 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 32.1 g (62.6 mmol) Yield 73%
H-NMR (CDCl3) δ1.42 (9H, s), 1.70-1.84 (2H, m), 1.86-2.00 (2H, m), 2.91-3.10 (2H, m), 3.38-3.53 (2H, m) , 3.70 (3H, s), 3.71-3.82 (2H, m), 4.40-4.44 (1H, m) 4.45-4.60 (1H, m), 4.93-5.00 (1H, m), 5.18 (2H, s), 6.92 (2H, d), 7.02 (2H, d), 7.13-7.21 (5H, m)
Process 4
Synthesis of benzyl 4- [4-[(2S) -2- (t-butoxycarbonylamino) -3-hydroxypropyl] phenoxy] piperidine-1-carboxylate
(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propionate (10.4 g, 20.3 mmol) in tetrahydrofuran (30 ml) Dissolve in 30 ml of methanol, add 2.44 g (64.5 mmol) of sodium borohydride at 0 ° C., return to room temperature and stir for 15 hours, then again add 0.82 g (21.7 mmol) of sodium borohydride at 0 ° C. In addition, the mixture was returned to room temperature and further stirred for 2 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 9.45 g (19.5 mmol) Yield 96%
H-NMR (CDCl3) δ 1.44 (9H, s), 1.68-1.82 (2H, m), 1.84-1.98 (2H, m), 2.78 (2H, d), 3.29-3.95 (7H, m), 4.40 -4.44 (1H, m), 5.14 (2H, s), 6.92 (2H, d), 7.12 (2H, d), 7.28-7.40 (5H, m)
Process 5
Synthesis of benzyl 4- [4-[(2S) -3-chloro-2- (t-butoxycarbonylamino) propyl] phenoxy] piperidine-1-carboxylate
4- [4-[(2S) -2- (t-butoxycarbonylamino) -3-hydroxypropyl] phenoxy] piperidine-1-carboxylate 5.5 g (11.3 mmol) was dissolved in dichloromethane 60 ml. At 0 ° C., 3.2 ml (22.6 mmol) of triethylamine and 1.95 g (17.0 mmol) of methanesulfonyl chloride were added. After stirring for 4 hours, dichloromethane was used as an extraction solvent and treated according to a conventional method to obtain an oily residue. The residue thus obtained was dissolved in 120 ml of dimethylformamide, 2.57 g (60.6 mmol) of lithium chloride was added, and the mixture was stirred at 50 ° C. for 15 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 2.60 g (5.16 mmol) Yield 45%
H-NMR (CDCl3) δ1.44 (9H, s), 1.63-1.82 (2H, m), 1.83-2.00 (2H, m), 2.91-3.10 (2H, m), 2.83 (2H, d), 3.40 -3.54 (3H, m), 3.57-3.63 (1H, m), 3.66-3.80 (3H, m), 4.40-4.52 (1H, m), 5.14 (2H, s), 6.92 (2H, d), 7.16 (2H, d), 7.13-7.21 (5H, m)
Step 6
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile
6.4 g (12.7 mmol) of benzyl 3- [4-[(2S) -3-chloro-2- (t-butoxycarbonylamino) propyl] phenoxy] piperidine-1-carboxylate was dissolved in 70 ml of dimethylformamide, 2.27 g (19.1 mmol) of 3-cyanophenol and 3.51 g (25.4 mmol) of potassium carbonate were added and stirred at 70 ° C. for 15 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 5.0 g (8.54 mmol) Yield 67%
H-NMR (CDCl3) δ1.44 (9H, s), 1.66-1.83 (2H, m), 1.84-2.00 (2H, m), 2.50-2.60 (1H, m), 2.82-2.93 (1H, m) , 3.40-3.53 (3H, m), 3.58-3.63 (1H, m), 3.65-3.80 (3H, m), 4.40-4.53 (1H, m), 5.14 (2H, s) 6.92 (2H, d), 7.16 (2H, d), 7.13-7.21 (5H, m)
Step 7
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (4-iodobenzenesulfonylamino) propoxy] benzonitrile 3-[(2S ) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile (2.54 g, 4.34 mmol) was converted into 4N chloride. 25 ml of hydrogen in dioxane and 12.5 ml of dioxane were added. After stirring at room temperature for 24 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 40 ml of dimethylformamide. 1.77 ml (13.0 mmol) of diisopropylethylamine and 1.97 g (6.51 mmol) of 4-iodobenzenesulfonyl chloride were added at 0 ° C. After 30 minutes, the mixture was returned to room temperature and stirred for 19 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 2.50 g (3.39 mmol) Yield 78%
H-NMR (CDCl3) δ 1.62-1.83 (2H, m), 1.63-2.00 (2H, m), 2.62-2.80 (1H, m), 2.83-3.00 (1H, m), 3.40-3.53 (2H, m), 3.62-3.80 (3H, m), 3.81-4.00 (2H, m), 4.40-4.45 (1H, m), 4.40-4.45 (1H, m), 5.14 (2H, s), 5.20-5.36 1H, m), 6.73 (2H, d), 6.90 (2H, d), 7.01 (2H, d), 7.24-7.44 (9H, m), 7.70 (2H, d)
Process 8
Synthesis of diethyl 4-[(1S) -2- (3-cyanophenoxy) -1- [4-[(1-benzyloxycarbonyl-4-piperidyl) oxy] phenylmethyl] ethyl] sulfamoyl] phenylphosphonate
To 310 mg (0.42 mmol) of 3-[(2S) -3- [4-[(1-benzyloxycarbonyl-4-piperidyl) oxy] phenyl] -2- (4-iodobenzenesulfonylamino) propoxy] benzonitrile , 0.59 ml (0.46 mmol) of diethyl phosphonate, 24 mg (0.02 mmol) of tetrakistriphenylphosphine palladium and 20 ml of triethylamine were added, and the mixture was stirred at 90 ° C. for 4 hours in the presence of argon. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 139 mg (0.18 mmol) Yield 43%
H-NMR (CDCl3) δ1.34 (6H, t), 1.68-1.83 (2H, m), 1.84-2.00 (2H, m), 2.76-2.94 (2H, m), 3.40-3.53 (2H, m) , 3.70-3.81 (3H, m), 3.82-3.95 (2H, m), 4.04-4.25 (4H, m), 4.38-4.52 (1H, m), 5.14 (2H, s), 6.76 (2H, d) , 6.92 (2H, d), 6.95-7.05 (3H, m), 7.32-7.39 (5H, m), 7.42-7.51 (1H, m) 7.63-7.71 (1H, m), 7.84 (2H, d), 7.87 (2H, d)
Step 9
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid monoethyl ditrifluoroacetate and
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid diethyl ditrifluoroacetate salt 4-[(1S ) -2- (3-cyanophenoxy) -1- [4-[(1-benzyloxycarbonyl-4-piperidyl) oxy] phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid diethyl 139 mg (0.18 mmol) It melt | dissolved in the dioxane solution 4.5 ml of hydrogen chloride, and 0.5 ml of ethanol containing 30% of hydrogen chloride (w / v) was added. After stirring at room temperature for 96 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 24 ml of an ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 24 hours. The residue obtained by distilling off the solvent was added 18 ml of acetic acid containing 20% hydrogen bromide at 0 ° C. and stirred for 1 hour, then returned to room temperature and stirred for 7 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid monoethyl ditrifluoroacetate yield 29 mg (0.03 mmol) Yield 19%
MS (ESI, m / z) 579 (MH +)
H-NMR (DMSO-d6) δ 1.18 (3H, t), 1.68-1.90 (2H, m), 2.00-2.18 (2H, m), 2.56-2.70 (1H, m), 2.80-2.92 (1H, m), 3.01-3.21 (2H, m), 3.21-3.36 (2H, m), 3.64-3.76 (1H, m), 3.82 (2H, q), 3.96 (2H, d), 4.53-4.64 (1H, m), 6.80 (2H, d), 7.03 (2H, d), 7.08 (1H, br), 7.22 (1H, br), 7.37 (1H, dd), 7.46 (1H, dd) 7.68 (2H, d) , 7.70 (2H, br), 8.21 (1H, dd), 8.38-8.54 (1H, m), 9.00 (2H, br), 9.33 (2H, br)
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid diethyl ditrifluoroacetate salt Yield 19 mg (0.02 mmol) Yield 12%
MS (ESI, m / z) 645 (MH +)
H-NMR (DMSO-d6) δ 1.24 (6H, t), 1.70-1.87 (2H, m), 2.01-2.14 (2H, m), 2.54-2.69 (1H, m), 2.77-2.93 (1H, m), 2.98-3.18 (2H, m), 3.20-3.33 (2H, m), 3.62-3.74 (1H, m), 3.97 (2H, d), 4.04 (4H, dq), 4.53-4.64 (1H, m), 6.80 (2H, d), 7.03 (2H, dd), 7.08 (1H, br), 7.26 (1H, br), 7.37 (1H, dd), 7.48 (1H, dd) 7.74 (2H, d) , 7.76 (2H, br), 8.31 (1H, dd), 8.38-8.54 (1H, m), 9.02 (2H, br), 9.27 (2H, br)
Example 72
4-[(1S) -2- (3-amidinophenoxy) -1- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid diethyl ditrifluoroacetic acid Salt synthesis
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid diethyl ditrifluoroacetate 19 mg (0.02 mmol) The title compound was obtained in the same manner as in Example 44, using as a starting material. Yield 11 mg (0.01 mmol) Yield 55%
MS (ESI, m / z) 686 (MH +)
H-NMR (DMSO-d6) δ 1.14 (6H, t), 1.60-1.84 (2H, m), 1.93-2.14 (2H, m), 2.28 (3H, s), 2.54-2.71 (1H, m) , 2.78-2.93 (1H, m), 3.46-3.60 (2H, m), 3.62-3.77 (3H, m), 3.80 (4H, q), 3.98 (2H, d), 4.58-4.67 (1H, m) , 6.82 (2H, d), 7.05 (2H, d), 7.08 (1H, br), 7.23 (1H, br), 7.35 (1H, d), 7.47 (1H, dd) 7.67 (4H, dd), 8.21 (1H, dd), 8.73 (1H, br), 9.08 (2H, br), 9.10 (1H, br), 9.33 (2H, br)
Example 73
4-[(1S) -2- (3-amidinophenoxy) -1- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid monoethyl ditrifluoroacetic acid Salt synthesis
4-[(1S) -2- (3-amidinophenoxy) -1- [4- (4-piperidyloxy) phenylmethyl] ethyl] sulfamoyl] phenylphosphonate monoethyl 29 mg (0.03 mmol) The title compound was obtained in the same manner as in Example 44.
Yield 13 mg (0.01 mmol) Yield 43%
MS (ESI, m / z) 658 (MH +)
H-NMR (DMSO-d6) δ1.24 (3H, t), 1.67-1.85 (2H, m), 1.99-2.15 (2H, m), 2.29 (3H, s), 2.56-2.70 (1H, m) , 2.79-2.95 (1H, m), 3.47-3.61 (2H, m), 3.62-3.85 (3H, m), 3.97 (2H, d), 4.03 (2H, q), 4.59-4.71 (1H, m) , 6.82 (2H, d), 7.05 (2H, d), 7.09 (1H, br), 7.27 (1H, br), 7.42 (1H, d), 7.48 (1H, dd) 7.73 (2H, d), 7.76 (2H, br), 8.32 (1H, dd), 8.57 (1H, br), 9.06 (2H, br), 9.13 (1H, br), 9.32 (2H, br)
Example 74
4-[(1S) -2- (3-amidinophenoxy) -1- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid ditrifluoroacetate Synthesis of
[(1S) -2- (3-Amidinophenoxy) -1- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenylmethyl] ethyl] sulfamoyl] phenylphosphonic acid diethyl ditrifluoroacetate 8 mg 1 ml of concentrated hydrochloric acid was added to (0.009 mmol), and the mixture was stirred at 130 ° C. for 4 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 3 mg (0.004 mmol) Yield 39%
MS (ESI, m / z) 630 (MH +)
H-NMR (DMSO-d6) δ 1.62-1.83 (2H, m), 1.94-2.12 (2H, m), 2.28 (3H, s), 2.53-2.70 (1H, m), 2.78-2.86 (1H, m), 3.48-3.63 (2H, m), 3.65-3.80 (3H, m), 3.95 (2H, d), 4.58-4.70 (1H, m), 6.82 (2H, d), 7.03 (2H, d) , 7.07 (1H, br), 7.22 (1H, br), 7.34 (1H, d), 7.46 (1H, dd) 7.66 (2H, d), 7.78 (2H, br), 8.16 (1H, d), 8.66 (1H, br), 9.04 (2H, br), 9.09 (1H, br), 9.30 (2H, br)
Example 75
4-[(1S) -2- (3-amidinophenoxy) -1-[(4-amidinophenyl) methyl] ethyl] sulfamoyl] benzoic acid Synthesis of ditrifluoroacetate
Process 1
Synthesis of t-butyl [(1S) -2-hydroxy-1- (4-iodobenzyl) ethyl] carbamate
Under ice-cooling, 0.56 ml (7.73 mmol) of thionyl chloride was added to 3 ml of methanol, and then 450 mg (1.56 mmol) of L-4-iodophenylalanine was added and refluxed with heating for 2 hours. To the residue obtained by distilling off the solvent, 0.52 ml (4.68 mmol) of N-methylmorpholine, 443 mg (2.03 mmol) of di-t-butyl carbonate and 10 ml of dichloromethane were added and stirred for 19 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and 3 ml of methanol and 3 ml of tetrahydrofuran were added to the resulting residue. 143 mg (3.78 mmol) of sodium borohydride was added and stirred for 17 hours. The reaction mixture was slowly poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water, 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography to obtain the title compound.
Yield 240 mg (0.64 mmol) Yield 41%
H-NMR (CDCl3) δ1.42 (9H, s), 3.48-3.77 (2H, m), 2.59 (2H, d), 3.79-3.91 (2H, m), 4.63-4.78 (1H, m), 6.97 (2H, d), 7.64 (2H, d)
Process 3
Synthesis of [(1S) -2-chloro-1- (4-iodobenzyl) ethyl] t-butyl carbamate [(1S) -2-hydroxy-1- (4-iodobenzyl) ethyl] t-butyl carbamate Under ice-cooling, 360 mg (0.96 mmol) of dichloromethane was added with triethylamine 0.27 ml (1.92 mmol) and methanesulfonyl chloride 165 mg (1.44 mmol), stirred for 30 minutes, then returned to room temperature and stirred for 15 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed successively with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 10 ml of dimethylformamide, 203 mg of lithium chloride (4 mg .8 mmol) was added and the mixture was stirred at 50 ° C. for 19 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Yield 237 mg (0.60 mmol) Yield 63%
H-NMR (CDCl3) δ1.43 (9H, s), 2.80-2.93 (2H, m), 3.48 (1H, dd), 3.62 (1H, dd), 4.00-4.18 (1H, m), 7.00 (2H , d), 7.63 (2H, d)
Process 3
Synthesis of [(1S) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] t-butyl carbamate
[(1S) -2-Chloro-1- (4-iodobenzyl) ethyl] tert-butyl carbamate 237 mg (0.60 mmol), dimethylformamide 5 ml, 3-cyanophenol 107 mg (0.90 mmol), potassium carbonate 165 mg (1.2 mmol) was added and stirred at 70 ° C. for 19 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound. Yield 282 mg (0.59 mmol) Yield 63%
H-NMR (CDCl3) δ1.43 (9H, s), 2.93 (2H, d), 3.84-3.94 (2H, m), 4.73-4.89 (1H, m), 6.94 (2H, d), 7.09 (2H , d), 7.13 (1H, d), 7.38 (1H, dd), 7.60 (2H, d)
Process 4
Synthesis of t-butyl 4-[(1S) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] sulfamoyl] benzoate
117 mg (0.24 mmol) of [(1S) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] carbamate was added to 1.3 ml of a 4N hydrogen chloride in dioxane, and dioxane was added in an amount of 0. Dissolved in 63 ml and stirred for 3 hours. The residue obtained by distilling off the solvent was dissolved in 5 ml of dimethylformamide. Under ice cooling, 0.13 ml (0.73 mmol) of diisopropylethylamine and 135 mg (0.49 mmol) of t-butyl 4-chlorosulfonylbenzoate were added. The mixture was stirred for 30 minutes. It returned to room temperature and stirred for 19 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. (Note that t-butyl 4-chlorosulfonylbenzoate was obtained by reacting in dichloromethane with chlorosulfonylbenzoic acid, isobutene and concentrated sulfuric acid and treating in accordance with a conventional method). The organic layer was washed successively with water and saturated brine, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Yield 50 mg (0.08 mmol) Yield 33%
H-NMR (CDCl3) δ1.63 (9H, s), 2.71-2.82 (1H, m), 2.86-2.99 (1H, m), 5.15-5.28 (1H, m), 7.07 (2H, br), 7.20 (2H, d), 7.27 (1H, dd), 7.34 (1H, dd), 7.45 (2H, d), 7.69 (2H, d), 7.98 (2H, d)
Process 5
Synthesis of t-butyl 4-[(1S) -2- (3-cyanophenoxy) -1- (4-cyanobenzyl) ethyl] sulfamoyl] benzoate
4-[(1S) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] sulfamoyl] benzoic acid t-butyl 50 mg (0.08 mmol) was added to N-methyl-2-pyrrolidone 0.5 ml. Then, 11 mg (0.01 mmol) of copper (I) cyanide was added, and the mixture was stirred at 130 ° C. for 7 hours in the presence of argon. The reaction solution was purified by silica gel column chromatography to obtain the title compound.
Yield 21 mg (0.04 mmol) Yield 33%
H-NMR (CDCl3) δ1.63 (9H, s), 2.82-3.10 (1H, m), 3.90 (2H, br), 5.06-5.13 (1H, m), 7.01 (2H, br), 7.15 (2H , d), 7.28 (1H, dd), 7.37 (1H, dd), 7.47 (2H, d), 7.74 (2H, d), 7.98 (2H, d)
Step 6
4-[(1S) -2- (3-amidinophenoxy) -1-[(4-amidinophenyl) methyl] ethyl] sulfamoyl] benzoic acid Synthesis of ditrifluoroacetate
Starting from 21 mg (0.04 mmol) of t-butyl 4-[(1S) -2- (3-cyanophenoxy) -1- (4-cyanobenzyl) ethyl] sulfamoyl] benzoate, the title compound was prepared according to the same procedure. Got.
Yield 3 mg (0.004 mmol) Yield 10%
MS (ESI, m / z) 496 (MH +)
H-NMR (DMSO-d6) δ2.42-2.60 (1H, m), 2.72-2.84 (1H, m), 3.48-3.61 (1H, m), 3.77 (2H, dd), 6.88 (2H, dd) , 7.01 (1H, br), 7.08 (2H, d), 7.12 (1H, dd), 7.23 (1H, t), 7.33 (2H, d), 7.38 (1H, br), 7.60 (2H, d), 8.08-8.15 (1H, m), 8.63 (2H, br), 8.73 (1H, br), 8.93 (2H, br), 9.02 (2H, br)
Example 76
N- [2- (3-Amidinophenoxy) ethyl] -N-benzyl-4-[(piperidin-4-yl) oxy] benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (1-t-butoxycarbonyl-4-piperidyloxy) benzamide
Starting from 211.2 mg (0.65 mmol) 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoic acid and 129.2 mg (0.65 mmol) 3- (2-aminoethoxy) benzonitrile hydrochloride The title compound was obtained in the same manner as in Example 1, Step 4.
Yield 167 mg (0.36 mmol) Yield 55%
H-NMR (CDCl3) δ 1.50 (9H, s), 1.65-1.80 (2H, m), 1.85-2.00 (2H, m), 3.30-3.40 (2H, m), 3.60-3.75 (2H, m) , 3.90 (2H, dt), 4.20 (2H, t), 4.55 (1H, m), 6.45 (1H, t), 6.94 (2H, d), 7.15 (1H, d), 7.17 (1H, s), 7.26 (1H, d), 7.38 (1H, t), 6.74 (2H, d)
Process 2
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -N-benzyl-4- (1-t-butoxycarbonylpiperidin-4-yl) oxybenzamide
236 mg (5.91 mmol) of sodium hydride (60% oily) was stirred in dimethylformamide under ice cooling. 2.67 g (5.91 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4- (1-t-butoxycarbonylpiperidin-4-yl) oxybenzamide dissolved in a small amount of dimethylformamide was added. . After the generation of hydrogen was over, 1.4 ml (11.8 mmol) of benzyl bromide was added, followed by stirring at room temperature for 2 hours. After evaporating the solvent under reduced pressure, 1N hydrogen chloride was added, and ethyl acetate was used as an extraction solvent, followed by a conventional process to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 2.85 g (5.26 mmol) Yield 89%
H-NMR (CDCl3) δ1.43 (9H, s), 1.72-1.80 (2H, m), 1.85-1.93 (2H, m), 3.23-3.38 (2H, m), 3.60-3.70 (2H, m) , 3.72-3.81 (2H, m), 4.15-4.22 (2H, m), 4.47-4.50 (1H, m), 4.77 (2H, brs), 6.88 (1H, d), 7.09 (1H, m), 7.25 (1H, brs), 7.26-7.50 (7H, m), 7.58 (1H, d), 7.68 (1H, t), 8.01 (1H, s)
Process 3
N- [2- (3-Amidinophenoxy) ethyl] -N-benzyl-4-[(piperidin-4-yl) oxy] benzamide Synthesis of ditrifluoroacetate
2.85 g (5.26 mmol) of N- [2- (3-cyanophenoxy) ethyl] -N-benzyl-4- (1-t-butoxycarbonylpiperidin-4-yl) oxybenzamide containing 4N hydrogen chloride The mixture was stirred in 5 ml of dioxane, added with 5 ml of ethanol containing 30% hydrogen chloride (w / v) and stirred at room temperature for 5 days. The solvent was distilled off under reduced pressure, and the resulting residue contained 10% ammonia (w / V) Dissolved in 15 ml of ethanol solution and stirred at room temperature for 1 day. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by lyophilizing the fraction of interest by elution with a mixed solvent of water and acetonitrile.
Yield 1.25 g (1.78 mmol) Yield 34%
MS (ESI, m / z) 473 (MH +)
H-NMR (DMSO-d6) δ 1.79-1.83 (2H, m), 2.05-2.11 (2H, m), 3.06-3.11 (2H, m), 3.22-3.27 (2H, m), 3.63-3.68 ( 2H, m), 4.15-4.29 (2H, m), 4.69-4.77 (3H, m), 7.04 (2H, d), 7.20-7.60 (10H, m), 7.50 (1H, t), 8.60 (2H, brs), 9.26 (4H, d)
Example 77
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -N-benzyl-4- (1-acetyl-piperidin-4-yl) oxybenzamide trifluoroacetate
N- [2- (3-Amidinophenoxy) ethyl] -N-benzyl-4-[(piperidin-4-yl) oxy] benzamide 180 mg (0.257 mmol) ditrifluoroacetate, 0.12 ml triethylamine (0. 848 mmol) was stirred in 1 ml of pyridine under ice cooling, 0.02 ml (0.283 mmol) of acetyl chloride was slowly added thereto and stirred for 3 days. After returning to room temperature, the solvent is distilled off, and the resulting residue is subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contains 0.1% of trifluoroacetic acid. (V / v) The title compound was obtained by elution with a mixed solvent of water and acetonitrile and freeze-drying the fraction of interest.
Yield 73.5 mg (0.12 mmol) Yield 46%
MS (ESI, m / z) 515 (MH +)
H-NMR (DMSO-d6) δ1.41-1.62 (2H, m), 1.85-2.00 (2H, m), 2.01 (3H, s), 3.23 (2H, dt), 3.60-3.65 (2H, m) , 3.80-3.90 (1H, m), 4.20-4.30 (2H, m), 4.60-4.70 (2H, m), 4.75 (2H, brs), 7.03 (2H, d), 7.20-7.43 (10H, m) 7.52 (1H, t), 9.21 (4H, d)
Example 78
N- [2- (3-Amidinophenoxy) ethyl] -N-benzyl-4- [1- (aminoacetyl) -piperidin-4-yl] oxybenzamide Synthesis of ditrifluoroacetate
40 mg (0.314 mmol) of Nt-butoxycarbonylglycine was stirred in dimethylformamide, and 0.1 ml (0.69 mmol) of triethylamine and 0.03 ml (0.314 mmol) of ethyl chloroformate were added under ice cooling and stirred for 5 minutes. Then N- [2- (3-amidinophenoxy) ethyl] -N-benzyl-4-[(piperidin-4-yl) oxy] benzamide 220 mg (0.314 mmol) ditrifluoroacetate was added. After returning to room temperature and stirring for 4 hours, the solvent was distilled off to obtain a crude product. The crude product was stirred in 0.5 ml of dioxane containing 4N hydrogen chloride for 28 hours at room temperature. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 61.6 mg (0.0813 mmol) Yield 26%
MS (ESI, m / z) 530 (MH +)
H-NMR (DMSO-d6) δ 1.50-1.70 (2H, m), 1.91-2.10 (2H, m), 3.05-3.10 (1H, m), 3.20-3.40 (2H, m), 3.52-3.70 ( 3H, m), 3.80-4.00 (2H, m), 4.23 (2H, m), 4.72 (2H, brs), 7.05 (2H, d), 7.20-7.52 (10H, m), 7.53 (1H, t) , 8.03 (3H, brs), 9.28 (4H, d)
Example 79
3- [4-Amidino-2- [2- [4- (1-acetimidoyl-4-piperidyloxy) benzoylamino] ethoxy] phenyl] -2-oxopropionic acid Synthesis of ditrifluoroacetate
Process 1
Synthesis of 3-hydroxy-4-iodobenzoic acid
30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid, and 53.0 g (326 mmol) of iodine monochloride was added at room temperature. After stirring at 45 ° C. for 15 hours, the residue obtained by distilling off the solvent under reduced pressure was washed twice with 500 ml of 1% aqueous sodium thiosulfate solution and twice with 500 ml of water, and dried at 80 ° C. under reduced pressure to give the title compound. Got.
Yield 17.2 g (65.2 mmol) Yield 30%
MS (FAB, m / z) 265 (MH +)
H-NMR (DMSO-d6) δ7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
Process 2
Synthesis of 3-hydroxy-4-iodobenzonitrile
To a solution of 22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid in 300 ml of tetrahydrofuran, 19.7 ml (206 mmol) of ethyl chloroformate and 28.7 ml (206 mmol) of triethylamine were added at 0 ° C. After stirring for 15 minutes, the produced triethylamine hydrochloride was filtered off, and the filtrate was added at 0 ° C. to 300 ml of a tetrahydrofuran solution obtained by bubbling ammonia. After stirring at room temperature for 10 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 450 ml of dioxane, and 17.4 ml (117 mmol) of trifluoromethanesulfonic anhydride and 21.8 ml (269 mmol) of pyridine were added at 0 ° C. . After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the resulting residue was treated according to a conventional method using chloroform as an extraction solvent to obtain an oily residue. To a solution of the obtained residue in 180 ml of tetrahydrofuran: methanol (1: 1), 1N aqueous sodium hydroxide solution (90 ml, 90.0 mmol) was added at room temperature. After stirring for 4 hours, the solvent was distilled off under reduced pressure, and the resulting residue was washed with dichloromethane. Subsequently, the mixture was acidified with 1N hydrogen chloride and treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 9.29 g (37.9 mmol) Yield 42%
MS (FAB, m / z) 246 (MH +)
H-NMR (CDCl3) δ5.63 (1H, br), 6.96 (1H, dd), 7.23 (1H, d), 7.79 (1H, d)
Process 3
Synthesis of 3- (2-aminoethoxy) -4-iodobenzonitrile hydrochloride
Using 3-hydroxy-4-iodobenzonitrile and t-butyl (2-chloroethyl) carbamate as starting materials, the title compound was obtained in the same manner as in Step 2 and Step 3 of Example 1. T-Butyl (2-chloroethyl) carbamate was obtained in the same manner as in Step 1 of Example 1 using 2-chloroethylamine hydrochloride.
Process 4
Synthesis of N- [2- (5-cyano-2-iodophenoxy) ethyl] -4- (1-t-butoxycarbonyl-4-piperidyloxy) benzamide
3- (2-Aminoethoxy) -4-iodobenzonitrile hydrochloride 2.28 g (7.03 mmol), 4-[(1-t-butoxycarbonyl-4-piperidyl) oxy] benzoic acid 2.90 g (9. 02 mmol), 11.1 g (85.9 mmol) of diisopropylethylamine, 3.02 g (15.8 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 0.62 g (5. 07 mmol) was dissolved in 80 ml of dimethylformamide and stirred overnight at room temperature. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 2.72 g (4.60 mmol) Yield 65.4%
H-NMR (CDCl3) δ1.43 (9H, s), 1.62-1.82 (2H, m), 1.89-2.00 (2H, m), 3.30-3.40 (2H, m), 3.62-3.78 (2H, m) , 3.95 (2H, dt), 4.22 (2H, t), 4.55 (1H, m), 6.64 (1H, t), 6.94 (2H, d), 7.01 (1H, d), 7.03 (1H, dd), 7.78 (2H, d), 7.89 (1H, d)
Process 5
Synthesis of methyl 2-acetylamino-3- [4-cyano-2- [2- [4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoylamino] ethoxy] phenyl] acrylate
N- [2- (5-Cyano-2-iodophenoxy) ethyl] -4- (1-t-butoxycarbonyl-4-piperidyloxy) benzamide (2.72 g, 4.60 mmol), methyl 2-acetaminoacrylate 1.32 g (9.22 mmol) is dissolved in 80 ml of acetonitrile, 272 mg (1.21 mmol) of palladium (II) acetate, 630 mg (2.07 mmol) of tri-o-tolylphosphine, 1.71 g (9.23 mmol) of tributylamine And heated to reflux for 3 days. The solvent was distilled off and ethyl acetate was used as an extraction solvent, followed by a conventional method to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 1.12 g (1.85 mmol) Yield 40.2%
H-NMR (CDCl3) δ 1.45 (9H, s), 1.65-1.80 (2H, m), 1.85-2.00 (2H, m), 2.02 (3H, s), 3.30-3.40 (2H, m), 3.60 -3.75 (2H, m), 3.80 (3H, s), 4.35 (2H, t), 4.55 (1H, m), 6.82 (2H, d), 6.99 (1H, t), 7.18-7.22 (2H, m ), 7.33 (1H, s), 7.44 (1H, s), 7.69 (2H, d), 7.87 (1H, d)
Step 6
3- [4-Amidino-2- [2- [4- (1-acetimidoyl-4-piperidyloxy) benzoylamino] ethoxy] phenyl] -2-oxopropionic acid Synthesis of ditrifluoroacetate
2.12 g (1.85 mmol) methyl 2-acetylamino-3- [4-cyano-3- [2- [4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoylamino] ethoxy] phenyl] acrylate ) Was dissolved in 50 ml of 4N hydrogen chloride in dioxane, 5 ml of ethanol was added and stirred at room temperature for 10 days. The residue obtained by distilling off the solvent was dissolved in 80 ml of an ethanol solution containing 20% ammonia (w / v) and stirred at room temperature for 4 days. The solvent was distilled off, and the obtained residue was dissolved in ethylacetimidate hydrochloride 2.23 g (18.0 mmol) and triethylamine 16.0 g (158 mmol) in 100 ml of ethanol and stirred at 30 ° C. for 4 days. The crude product obtained by distilling off the solvent was dissolved in 50 ml of a mixed solvent of water and acetonitrile (41) containing 0.1% of trifluoroacetic acid, and octadodecyl group chemically bonded silica gel was used as a filler. It was subjected to reverse phase medium pressure preparative chromatography (LiChroprep RP-18 37 × 440 mm) and eluted with a mixed solvent of water and acetonitrile containing 0.1% of trifluoroacetic acid (v / v). The residue obtained by removing the solvent by lyophilization was dissolved in 50 ml of 6N hydrochloric acid and stirred at 80 ° C. for 2 hours. The crude product obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and freeze-drying the fraction of interest.
Yield 123 mg (0.167 mmol) Yield 9.0%
MS (ESI, m / z) 510 (MH +)
H-NMR (DMSO-d6) δ 1.65-1.85 (2H, m), 2.02-2.19 (2H, m), 2.25 (3H, s), 3.58-3.82 (6H, m), 4.23 (2H, s, keto form), 4.30 (2H, t), 4.79 (1H, m), 6.80 (1H, s, enol form), 7.07 (2H, d), 7.38-7.47 (2H, m), 7.83 (2H, d) , 8.33 (1H, d), 8.55-8.67 (2H, m), 9.05-9.34 (5H, brm), 9.75 (1H, br, enol form)
Example 80
Synthesis of 3- [4-amidino-2- [2- [4- (dimethylcarbamoyl) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid trifluoroacetate
Process 1
Synthesis of N- [2- (2-iodo-5-cyanophenoxy) ethyl] -4- (N, N-dimethylcarbamoyl) benzamide
4-Dimethylcarbamoylbenzoic acid 600 mg (3.1 mmol) and triethylamine 1.25 g were stirred in dimethylformamide. Thereto was added 336 mg (3.1 mmol) of ethyl chloroformate under ice-cooling, and the mixture was stirred for 5 minutes, and then 3- (2-aminoethoxy) -4-iodobenzonitrile monohydrochloride was added. After returning to room temperature and stirring for 2 hours, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with ethyl acetate to give the title compound. Further, the residue after evaporation of the solvent in the washing solution was purified by silica gel chromatography (ethyl acetate-methanol) to obtain the title compound.
Yield Total 983 mg (2.1 mmol) Yield 68%
H-NMR (DMSO-d6) δ 2.87 (3H, br), 3.00 (3H, br), 3.65 (2H, dt), 4.27 (2H, t), 7.17 (1H, d), 7.47 (2H, d ), 7.52 (1H, s), 7.88 (2H, d), 7.98 (1H, d), 8.67 (1H, br)
Process 2
Synthesis of methyl 2-acetylamino-3- [4-cyano-2- [2- [4- (dimethylcarbamoyl) benzoylamino] ethoxy] phenyl] acrylate
[2- (2-iodo-5-cyanophenoxy) ethyl] -4- (N, N-dimethylcarbamoyl) benzamide 968 mg (2.09 mmol), methyl 2- (acetylamino) acrylate 600 mg (4.18 mmol), Palladium (II) acetate 93 mg (0.38 mmol), tri-o-tolylphosphine 548 mg (1.8 mmol), and tributylamine 775 mg (4.18 mmol) were heated to reflux in acetonitrile for 2 days. The solvent was distilled off, methanol was added and the mixture was filtered through Celite, and then the solvent was distilled off. 1N Hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography (ethyl acetate-methanol) to give the title compound.
Yield 629 mg (1.3 mmol) Yield 62%
H-NMR (DMSO-d6) δ 1.95 (3H, s), 2.90 (3H, s), 3.00 (3H, s), 3.60-3.70 (5H, m), 4.30 (2H, t), 7.21 (1H , s), 7.43 (1H, d), 7.47 (2H, d), 7.63 (1H, s), 7.67 (1H, d), 7.87 (2H, d), 8.75 (1H, t), 9.65 (1H, s)
Process 3
Synthesis of 3- [4-amidino-2- [2- [4- (dimethylcarbamoyl) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid trifluoroacetate
2-acetylamino-3- [4-cyano-2- [2- [4- (dimethylcarbamoyl) benzoylamino] ethoxy] phenyl] methyl 620 mg (1.3 mmol) was added with 4N dioxane hydrochloride 5 ml and ethanol 1 ml. The mixture was stirred for 96 hours. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 10 ml of an ethanol solution containing 10% ammonia (w / v) and stirred for 24 hours. The residue obtained by distilling off the solvent under reduced pressure was dissolved in 5 ml of 6N hydrochloric acid and stirred at 80 ° C. for 2 hours. The residue obtained by distilling off the solvent under reduced pressure was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest. Yield 46 mg (0.08 mmol) Yield 6%
MS (ESI, m / z) 441 (MH +)
H-NMR (DMSO-d6) δ2.90 (3H, br), 3.00 (3H, br), 3.70 (2H, dt), 4.28 (2H, t), 4.23 (2H, s, keto form) 6.85 (1H , s, enol form) 7.35-7.50 (4H, m), 7.88 (2H, d), 8.33 (1H, d), 8.83 (1H, t), 9.00 (2H, br), 9.25 (2H, Br), 9.75 (1H, enol, s)
Example 81
Synthesis of 3- [4-amidino-2- [2- [4- (4-piperidylmethyl) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid ditrifluoroacetate
Process 1
Synthesis of 2-acetylamino-3- [4-cyano-2- [2- [4-[(1-t-butoxycarbonyl-4-piperidyl) methyl] benzoylamino] ethoxy] phenyl] -methyl acrylate 4- To 600 mg (1.80 mmol) of methyl [(1-t-butoxycarbonylpiperidin-4-yl) methyl] benzoate was added 4 ml of 1N sodium hydroxide and 6 ml of ethanol, and the mixture was stirred for 18 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the resulting residue was dissolved in 10 ml of dichloromethane, and 1.25 ml (9.06 mmol) of triethylamine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 378 mg (1.98 mmol) of salt, 267 mg (1.98 mmol) of 1-hydroxybenzotriazole and 202 mg (1.02 mmol) of 3- (2-aminoethoxy) -4-iodobenzonitrile hydrochloride were added and stirred for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was dissolved in 10 ml of acetonitrile to obtain methyl-2-acetamide. Add 478 mg (3.34 mmol) of door acrylate, 41 mg (0.17 mmol) of palladium (II) acetate, 355 mg (1.17 mmol) of tris (2-methylphenyl) phosphine, and 618 mg (3.34 mmol) of tributylamine and heat for 18 hours. Refluxed. After distilling off the solvent, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the title compound. It was.
Yield 530 mg (0.85 mmol) Yield 51%
H-NMR (CDCl3) δ1.04-1.17 (2H, m), 1.42 (9H, s), 1.58-1.77 (3H, m), 1.98 (3H, s), 2.54 (2H, d), 2.73-2.89 (2H, m), 3.78 (3H, s), 3.89 (2H, dt), 3.96-4.08 (2H, m), 4.31 (2H, t), 6.95-7.03 (1H, m), 7.11 (2H, d ), 7.12-7.19 (2H, m), 7.23-7.27 (1H, m), 7.29-7.34 (1H, m), 7.43 (1H, br), 7.63 (2H, d)
Process 2
Synthesis of 3- [4-amidino-2- [2- [4- (4-piperidylmethyl) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid ditrifluoroacetate
530 mg (0.85 mmol) methyl 2-acetylamino-3- [4-cyano-2- [2- [4-[(1-t-butoxycarbonyl-4-piperidyl) methyl] benzoylamino] ethoxy] phenyl] acrylate ) As a starting material, and the title compound was obtained in the same manner as in Step 3 of Example 80.
Yield 150 mg (0.22 mmol) Yield 25%
MS (ESI, m / z) 467 (MH +)
H-NMR (DMSO-d6) δ 1.23-1.40 (2H, m), 1.62-1.73 (2H, m), 1.76-1.90 (1H, m), 2.59 (2H, d), 2.72-2.91 (2H, m), 3.17-3.30 (2H, m), 3.68 (2H, dt), 4.21 (2H, s, keto form), 4.29 (2H, t), 6.82 (1H, s, enol form), 7.27 (2H, d), 7.34-7.49 (2H, m), 7.80 (2H, d), 8.34 (1H, d), 8.66-8.74 (1H, m), 9.12 (2H, br), 9.25 (2H, br), 9.78 (1H, br, enol form)
Example 82
Synthesis of 3- [4-amidino-2- [2- [4- (pyrrolidin-1-yl) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid trifluoroacetate
Process 1
Synthesis of methyl 2-acetylamino-3- [4-cyano-2- [2- [4- (pyrrolidin-1-yl) benzoylamino] ethoxy] phenyl] acrylate
400 mg (2.09 mmol) of 4- (pyrrolidin-1-yl) benzoic acid was dissolved in 10 ml of dichloromethane, and 1.25 ml (9.06 mmol) of triethylamine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 439 mg (2.30 mmol), 1-hydroxybenzotriazole 310 mg (2.30 mmol), 3- (2-aminoethoxy) -4-iodobenzonitrile hydrochloride 636 mg (2.09 mmol) were added, and the mixture was stirred for 19 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was dissolved in 15 ml of acetonitrile to give methyl-2-acetamide. Add 503 mg (3.51 mmol) of door acrylate, 43 mg (0.18 mmol) of palladium (II) acetate, 375 mg (1.23 mmol) of tris (2-methylphenyl) phosphine, and 649 mg (3.51 mmol) of tributylamine and heat for 18 hours. Refluxed. After distilling off the solvent, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the title compound. It was.
Yield 650 mg (1.37 mmol) Yield 78%
H-NMR (CDCl3) δ1.92-2.10 (7H, m), 3.11-3.28 (3H, m), 3.74-3.83 (5H, m), 4.24 (2H, t), 6.45 (2H, d), 6.65 -6.73 (1H, m), 7.18 (1H, d), 7.24 (1H, br), 7.31-7.42 (2H, m), 7.61 (2H, d)
Process 2
Synthesis of 3- [4-amidino-2- [2- [4- (pyrrolidin-1-yl) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid trifluoroacetate
650 mg (1.37 mmol) of methyl 2-acetylamino-3- [4-cyano-2- [2- [4- (pyrrolidin-1-yl) benzoylamino] ethoxy] phenyl] acrylate was treated with Example 80 Step 3. The title compound was obtained according to the same procedure.
Yield 130 mg (0.24 mmol) Yield 17%
MS (ESI, m / z) 439 (MH +)
H-NMR (DMSO-d6) δ1.88-2.04 (4H, m), 3.23-3.35 (4H, m), 3.67 (2H, dt), 4.21 (2H, s, keto form), 4.23 (2H, t ), 6.52 (2H, d), 6.82 (1H, s, enol form), 7.31-7.52 (2H, m), 7.72 (2H, d), 8.27-8.39 (2H, m), 9.00 (2H, br) , 9.26 (2H, br), 9.78 (1H, br, enol form)
Example 83
(4S) -4- (4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoic acid ditrifluoroacetate and
Synthesis of ethyl (4S) -4- (4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoate ditrifluoroacetate
Process 1
Synthesis of (4S) -4-t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoic acid benzyl
The title compound was obtained in the same manner as in Step 1 of Example 51 using 6.75 g (20.0 mmol) of Nt-butoxycarbonyl-L-glutamic acid-γ-benzyl ester as a starting material.
Yield 6.90 g (16.3 mmol) Yield 81%
H-NMR (CDCl3) δ 1.44 (9H, s), 1.69 (2H, br), 2.02 (2H, br), 3.98 (2H, br), 4.83 (1H, br), 5.11 (2H, s), 7.04-7.16 (4H, m), 7.24-7.40 (5H, m)
Process 2
Synthesis of benzyl (4S) -4- (4-cyanobenzoylamino) -5- (3-cyanophenoxy) pentanoate
Starting from 6.90 g (16.3 mmol) of benzyl (4S) -4-t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoate, the title compound was obtained in the same manner as in Step 2 of Example 51. It was.
Yield 3.56 g (7.85 mmol) Yield 48%
H-NMR (CDCl3) δ 2.10-2.28 (2H, m), 2,54 (1H, ddd), 2.69 (1H, ddd), 4.10 (1H, dd), 4.18 (1H, dd), 4.48 (1H , br), 5.12 (2H, s), 7.00 (1H, br), 7.14-7.19 (2H, m), 7.24-7.41 (7H, m), 7.72 (2H, d), 7.87 (2H, d)
Process 3
Synthesis of ethyl (4S) -4- (4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoate ditrifluoroacetate
Starting from 3.56 g (7.85 mmol) of benzyl (4S) -4- (4-cyanobenzoylamino) -5- (3-cyanophenoxy) pentanoate, the title compound was prepared in the same manner as in Step 3 of Example 51. Got.
Yield 2.19 g (3.35 mmol) Yield 43%
MS (ESI, m / z) 426 (MH +)
H-NMR (DMSO-d6) δ 1.15 (3H, t), 1.88-1.98 (1H, m), 2.01-2.11 (1H, m), 2.45 (2H, ddd), 4.03 (2H, q), 4.11 (1H, dd), 4.19 (1H, dd), 4.38 (1H, br), 7.34 (1H, d), 7.39 (1H, d), 7.40 (1H, s), 7.54 (1H, dd), 7.91 ( 2H, d), 8.05 (2H, d), 8.66 (1H, d), 9.17 (2H, s), 9.29 (4H, s), 9.42 (2H, s)
Process 4
(4S) -4- (4-Amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoic acid Synthesis of ditrifluoroacetate
(4S) -4- (4-Amidinobenzoylamino) -5- (3-amidinophenoxy) ethyl pentanoate The same as in Example 51, Step 4, starting from 1.57 g (2.40 mmol) of ditrifluoroacetate To give the title compound. Yield 424 mg (0.677 mmol) Yield 28%
MS (ESI, m / z) 398 (MH +)
H-NMR (DMSO-d6) δ 1.84-1.96 (1H, m), 1.98-2.10 (1H, m), 2.37 (2H, ddd), 4.11 (1H, dd), 4.20 (1H, dd), 4.38 (1H, br), 7.33 (1H, d), 7.39 (1H, d), 7.40 (1H, s), 7.91 (2H, d), 8.05 (2H, d), 8.65 (1H, d), 9.18 ( 2H, s), 9.26 (2H, s), 9.29 (2H, s), 9.41 (2H, s)
Example 84
(4R) -4- (4-Carbamoylbenzoylamino) -5- (3-amidinophenoxy) pentanoic acid Synthesis of ditrifluoroacetate
Process 1
Synthesis of (4R) -4-t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoic acid benzyl
The title compound was obtained in the same manner as in Step 51 of Example 51 using 3.37 g (10.0 mmol) of Nt-butoxycarbonyl-D-glutamic acid-γ-benzyl ester as a starting material.
Yield 3.20 g (7.54 mmol) Yield 75%
H-NMR (CDCl3) δ 1.44 (9H, s), 1.69 (2H, br), 2.02 (2H, br), 3.98 (2H, br), 4.83 (1H, br), 5.11 (2H, s), 7.04-7.16 (4H, m), 7.24-7.40 (5H, m)
Process 2
Synthesis of (4R) -4- (4-cyanobenzoylamino) -5- (3-cyanophenoxy) pentanoic acid benzyl
Starting from 3.20 g (7.54 mmol) of benzyl (4R) -4-t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoate, the title compound was obtained in the same manner as in Step 2 of Example 51. It was.
Yield 2.16 g (4.76 mmol) Yield 63%
H-NMR (CDCl3) δ 2.10-2.28 (2H, m), 2,54 (1H, ddd), 2.69 (1H, ddd), 4.10 (1H, dd), 4.18 (1H, dd), 4.48 (1H , br), 5.12 (2H, s), 7.00 (1H, br), 7.14-7.19 (2H, m), 7.24-7.41 (7H, m), 7.72 (2H, d), 7.87 (2H, d)
Process 3
(4R) -4- (4-Carbamoylbenzoylamino) -5- (3-amidinophenoxy) pentanoic acid Synthesis of ditrifluoroacetate
The title compound was obtained in the same manner as in Example 2, Step 2, using benzyl (4R) -4- (4-cyanobenzoylamino) -5- (3-cyanophenoxy) pentanoate as the starting material.
MS (ESI, m / z) 399 (MH +)
H-NMR (DMSO-d6) δ 1.90 (1H, br), 2.01 (1H, br), 2.36 (2H, br), 4.08 (1H, dd), 4.17 (1H, dd), 4.36 (1H, br ), 7.35 (1H, d), 7.39 (1H, d), 7.41 (1H, s), 7.53 (1H, t), 7.92 (2H, d), 7.96 (2H, d), 8.08 (2H, br) , 8.50 (1H, d), 9.14 (2H, br), 9.27 (2H, br)
Example 85
N- [2- (3-Amidinophenoxy) ethyl] -N-benzyl-4- (1-acetimidoylpiperidin-4-yl) oxybenzamide Synthesis of ditrifluoroacetate
N- [2- (3-amidinophenoxy) ethyl] -N-benzyl-4- (piperidin-4-yl) oxybenzamide 230 mg (0.34 mmol) of ditrifluoroacetate was dissolved in 3 ml of ethanol, and triethylamine 0. 25 ml (1.74 mmol) and 87 mg (0.71 mmol) of ethyl acetimidate hydrochloride were added and stirred at room temperature for 6 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 196 mg (0.269 mmol) Yield 81%
MS (ESI, m / z) 473 (MH +)
H-NMR (DMSO-d6) δ1.65-1.80 (2H, m), 2.00-2.10 (2H, m), 2.31 (3H, s), 3.52 (2H, t), 3.57-3.80 (3H, m) 4.12-4.30 (2H, m), 4.60-4.80 (4H, m), 7.01 (2H, d), 7.20-7.40 (10H, m), 7.50 (1H, t), 8.62 (1H, s), 9.17 (1H, s), 9.32 (4H, brs)
Example 86
N-[(1R) -1-benzyl-2- (3-amidinophenoxy) ethyl] -4- (pyrrolidin-1-yl) benzamide Synthesis of ditrifluoroacetate
D-Phenylalanine methyl ester Hydrochloric acid hydrochloride was treated in the same manner as in Example 71, Step 2, to obtain methyl (2R) -2- (t-butoxycarbonylamino) -3-phenylpropionate. This was converted to t-butyl (1R) -1-benzyl-2-hydroxyethylcarbamate in the same manner as in Example 71, Step 4, and (1R) -1-benzyl- was converted in the same manner as in Example 71, Step 5 and Step 6. T-Butyl 2- (3-cyanophenoxy) ethylcarbamate was obtained. The title compound was obtained in the same manner as in Example 59 using 1.55 g (4.40 mmol) of t-butyl (1R) -1-benzyl-2- (3-cyanophenoxy) ethylcarbamate.
Yield 568 mg (1.02 mmol) Yield 23.2%
MS (ESI, m / z) 443 (MH +)
H-NMR (DMSO-d6) δ 1.82-2.01 (4H, m), 2.92-3.10 (2H, m), 3.18-3.37 (4H, m), 4.05 (1H, dd), 4.19 (1H, dd) , 4.42-4.57 (1H, m), 6.53 (2H, d), 7.15-7.42 (8H, m), 7.55 (1H, dd), 7.67 (2H, d), 8.08 (1H, d), 9.22 (2H , brs), 9.27 (2H, brs)
Example 87
N-[(1R) -2- (3-amidinophenoxy) -1- (4-hydroxybenzyl) ethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of (2R) -2- (t-butoxycarbonyl) amino-2- [4- (ethoxycarbonyloxy) benzyl] ethanol
Starting from 3.5 g (19.3 mmol) of D-tyrosine and t-butoxycarbonylated with di-t-butyldicarbonate, (2R) -2- (t-butoxycarbonyl) amino-3- [4-hydroxy Phenyl] propionic acid, mixed acid anhydride with ethyl chloroformate and diisopropylethylamine, and then reduced with sodium borohydride to give the title compound. Yield 5.72g
H-NMR (CDCl3) δ1.38 (3H, t), 1.42 (9H, s), 2.83 (2H, d), 3.58 (1H, dd), 3.65 (1H, dd), 3.78-3.88 (1H, m ), 4.28 (2H, q), 4.73 (1H, d), 7.11 (2H, d), 7.22 (2H, d)
Process 2
N-[(1R) -2- (3-amidinophenoxy) -1- (4-hydroxybenzyl) ethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Similar to Example 71, Step 5 and Step 6, using 5.72 g of the crude product (2R) -2- (t-butoxycarbonyl) amino-2- [4- (ethoxycarbonyloxy) benzyl] ethanol obtained in Step 1. Then, (1R) -1- [4- (ethoxycarbonyloxy) benzyl] -2- (3-cyanophenoxy) ethylcarbamate t-butyl was obtained. This was carried out in the same manner as in Example 51, Step 2, and then in the same manner as in Example 1, Step 6 to obtain the title compound.
Yield 16.5mg
MS (ESI, m / z) 432 (MH +)
H-NMR (DMSO-d6) δ 2.83 (1H, dd), 2.97 (1H, dd), 4.10-4.23 (2H, m), 4.43-4.57 (1H, m), 6.63 (2H, d), 7.10 (2H, d), 7.28 (1H, dd), 7.36-7.41 (2H, m), 7.58 (1H, dd), 7.90 (2H, d), 8.01 (2H, d), 8.75 (1H, d), 9.25 (2H, s), 9.31 (2H, s), 9.38 (2H, s), 9.41 (2H, s)
Example 88
N-[(1R) -1- (4-iodobenzyl) -2- (3-amidinophenoxy) ethyl] -4-amidinobenzamide ditrifluoroacetate and
4-[(2R) -2- (4-Amidinobenzoylamino) -3- (3-amidinophenoxy) propyl] methyl benzoate Synthesis of ditrifluoroacetate
Process 1
Synthesis of D-4-iodophenylalanine
In 20 g of D-phenylalanine (121 mmol), 14.5 ml of concentrated sulfuric acid, and 110 ml of acetic acid, 12.3 g (48 mmol) of iodine and 5.1 g (24 mmol) of sodium iodate were added and stirred for 24 hours. After cooling, 0.5 g of sodium periodate was added, and the solvent was distilled off under reduced pressure at 35 ° C. Water was added and washed twice with dichloromethane. The water bath was neutralized with 1N sodium hydroxide, and after cooling, the precipitate was filtered and washed with water and ethanol to obtain a crude product.
Yield 30 g (103 mmol) Yield 85%
Process 2
Synthesis of methyl (2R) -2-t-butoxycarbonylamino-3- (4-iodophenyl) propionate
Under ice cooling, 17 ml (230 mmol) of thionyl chloride was added to 3 ml of methanol, 22.2 g (76.3 mmol) of D-4-iodophenylalanine was added, and the mixture was heated to reflux for 2 hours. To the residue obtained by distilling off the solvent, 15 ml (137 mmol) of N-methylmorpholine, 12 g (55 mmol) of di-t-butyl carbonate and 100 ml of dichloromethane were added and stirred for 19 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound. .
Yield 12.2 g (35.8 mmol) Yield 47%
H-NMR (CDCl3) δ1.42 (9H, s), 2.83-3.18 (2H, m), 3.71 (3H, s), 4.43-4.60 (2H, m), 4.84-5.06 (1H, m), 6.85 (2H, d), 7.60 (2H, d)
Process 3
Synthesis of t-butyl [(1R) -2-chloro-1- (4-iodobenzyl) ethyl] carbamate 6.2 g methyl (2R) -t-butoxycarbonylamino-3- (4-iodophenyl) propionate 25 ml of methanol and 25 ml of tetrahydrofuran were added to (18 mmol), and 3.44 g (91 mmol) of sodium borohydride was added under ice cooling, followed by stirring for 17 hours. The reaction mixture was slowly poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water, 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and 50 ml of dichloromethane was added to the resulting residue. Then, 5.02 ml (36 mmol) of triethylamine and 3.09 g (27 mmol) of methanesulfonyl chloride were added and stirred for 30 minutes, then returned to room temperature and stirred for 15 hours. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed successively with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 40 ml of dimethylformamide and 3.85 g of lithium chloride. (91 mmol) was added and stirred at 50 ° C. for 19 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound.
Yield 3.4 g (8.6 mmol) Yield 47%
H-NMR (CDCl3) δ1.43 (9H, s), 2.80-2.93 (2H, m), 3.48 (1H, dd), 3.62 (1H, dd), 4.00-4.18 (1H, m), 7.00 (2H , d), 7.63 (2H, d)
Process 4
Synthesis of [(1R) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] t-butyl carbamate
[(1R) -2-chloro-1- (4-iodobenzyl) ethyl] t-butyl carbamate 1.6 g (0.60 mmol), dimethylformamide 25 ml, 3-cyanophenol 724 mg (6.08 mmol), carbonic acid 1.12 g (8.1 mmol) of potassium was added and stirred at 70 ° C. for 55 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound. Yield 1.44 g (3.01 mmol) Yield 74%
H-NMR (CDCl3) δ1.43 (9H, s), 2.93 (2H, d), 3.84-3.94 (2H, m), 4.73-4.89 (1H, m), 6.94 (2H, d), 7.09 (2H , d), 7.13 (1H, d), 7.38 (1H, dd), 7.60 (2H, d)
Process 5
Synthesis of N-[(1R) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] -4-cyanobenzamide
1.44 g (3.01 mmol) of [(1R) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] carbamate dissolved in 5 ml of 4N dioxane hydrochloride and 2.5 ml of dioxane And stirred for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 10 ml of dichloromethane. 488 mg (3.3 mmol) of 4-cyanobenzoic acid, 1.3 ml (9.3 mmol) of triethylamine, 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride 633 mg (1.5 mmol) and 1-hydroxybenzotriazole 445 mg (3.3 mmol) were added and stirred for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water, 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the title compound. It was.
Yield 1.51 g (3.00 mmol) Yield 99%
H-NMR (CDCl3) δ 3.03-3.17 (2H, m), 3.97-4.18 (2H, m), 4.62-4.77 (1H, m), 7.00 (2H, d), 7.18 (2H, dd), 7.30 (1H, dd), 7.41 (1H, dd), 7.61 (2H, d), 7.77 (2H, d), 7.83 (2H, d)
Step 6
N-[(1R) -1- (4-iodobenzyl) -2- (3-amidinophenoxy) ethyl] -4-amidinobenzamide ditrifluoroacetate and
4-[(2R) -2- (4-Amidinobenzoylamino) -3- (3-amidinophenoxy) propyl] methyl benzoate Synthesis of ditrifluoroacetate
After performing carbonylation in the same manner as in Example 39, Step 1 using N-[(1R) -2- (3-cyanophenoxy) -1- (4-iodobenzyl) ethyl] -4-cyanobenzamide as a starting material. The title compound was obtained in the same manner as in Example 1, Step 6.
4-Amidino-N-[(2R)-(3-amidinophenoxy) -1- (iodobenzyl) ethyl] benzamide ditrifluoroacetate
Yield 8 mg (0.015 mmol) Yield 1%
MS (ESI, m / z) 543 (MH +)
H-NMR (DMSO-d6) δ 2.86-3.12 (2H, m), 4.13-4.27 (2H, m), 4.48-4.62 (1H, m), 7.12 (2H, d), 7.30-7.45 (3H, m), 7.54 (1H, dd), 7.62 (2H, d), 7.88 (2H, d), 7.96 (2H, d), 8.78 (1H, d), 9.12 (2H, br), 9.22 (2H, br ), 9.28 (2H, br) 9.39 (2H, br)
4-[(2R)-(4-Amidinobenzoylamino) -3- (3-amidinophenoxy) -2-propyl] benzoic acid methyl ditrifluoroacetate
Yield 47 mg (0.067 mmol) Yield 7%
MS (ESI, m / z) 474 (MH +)
H-NMR (DMSO-d6) δ 3.02-3.25 (2H, m), 3.81 (3H, s), 4.17-4.28 (2H, m), 4.55-4.71 (1H, m), 7.32-7.50 (2H, m), 7.55 (1H, dd), 7.87 (4H, dd), 7.95 (2H, d), 8.80 (1H, d), 9.10 (2H, br), 9.20 (2H, br), 9.28 (2H, br ) 9.38 (2H, br)
Example 89
N-[(1R) -2- (3-amidinophenoxy) -1- (3-indolylmethyl) ethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
D-tryptophan methyl ester hydrochloride 5.09 g (20.0 mmol) was used as a starting material, and the intermediate was purified and treated in the same manner as in Example 86 to obtain the title compound. However, 4-cyanobenzoic acid was used instead of 4- (pyrrolidin-1-yl) benzoic acid.
Yield 209 mg (0.306 mmol) Yield 1.5%
MS (ESI, m / z) 455 (MH +)
H-NMR (DMSO-d6) δ 3.02-3.12 (2H, m), 4.20-4.35 (2H, m), 4.60-4.88 (2H, m), 6.95-7.66 (13H, m), 7.85 (2H, d), 8.03 (2H, d), 8.81 (1H, d), 9.07-9.41 (8H, m), 10.81 (1H, s)
Example 90
4-[(2R) -2- (4-Amidinobenzoylamino) -3- (3-amidinophenoxy) propyl] benzoic acid Synthesis of ditrifluoroacetate
4-[(2R) -2- (4-amidinobenzoylamino) -3- (3-amidinophenoxy) propyl] benzoic acid methyl ditrifluoroacetate (8 mg, 0.011 mmol) was added with 5 ml of concentrated hydrochloric acid at 60 ° C. For 19 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 6 mg (0.009 mmol) Yield 80%
MS (FAB, m / z) 460 (MH +)
H-NMR (DMSO-d6) δ3.00-3.24 (2H, m), 4.46-4.26 (2H, m), 4.58-4.68 (1H, m), 7.33-7.48 (2H, m), 7.55 (1H, dd), 7.84 (2H, d), 7.87 (2H, d), 7.94 (2H, d), 8.79 (1H, d), 9.08 (2H, br), 9.18 (2H, br), 9.28 (2H, br ) 9.37 (2H, br)
Example 91
(2S) -2- (4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid Synthesis of ditrifluoroacetate
Process 1
Synthesis of benzyl (2S) -2-t-butoxycarbonylamino-4- (3-cyanophenoxy) butanoate
Nt-butoxycarbonyl-L-aspartic acid-α-benzyl ester 3.23 g (10.0 mmol) and triethylamine 1.39 ml (10.0 mmol) were dissolved in 50 ml of tetrahydrofuran, and 0.96 ml of ethyl chloroformate under ice-cooling. (10.0 mmol) was added and stirred for 20 minutes. The generated precipitate was removed by suction filtration, and 3 g of ice and 380 mg (10.0 mmol) of sodium borohydride were added to the filtrate under ice cooling, followed by stirring for 1.5 hours. 50 ml of 1N aqueous hydrogen chloride solution was added thereto, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. The oily residue thus obtained was dissolved in 30 ml of tetrahydrofuran, 737 mg (6.18 mmol) of 3-cyanophenol, 1.77 g (6.74 mmol) of triphenylphosphine, 2.70 g of diethyl azodicarboxylate (40% toluene solution) ( 6.18 mmol) was added and stirred at room temperature overnight. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 1.12 g (2.73 mmol) Yield 27%
H-NMR (CDCl3) δ1.40 (9H, s), 2.30 (2H, br), 4.05 (2H, t), 4.58 (1H, br), 5.20 (2H, t), 5.70 (1H, br), 7.0-7.2 (4H, m), 7.3 (5H, s)
Process 2
Synthesis of benzyl (2S) -2- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butanoate
1.12 g (2.73 mmol) of benzyl (2S) -2-t-butoxycarbonylamino-4- (3-cyanophenoxy) butanoate was dissolved in 10 ml of 4N hydrogen chloride in dioxane and stirred at room temperature for 2 hours. . The oily residue obtained by distilling off the solvent was dissolved in 14 ml of dichloromethane. Under ice cooling, 390 mg (2.73 mmol) of 4-cyanobenzoic acid, 405 mg (3.00 mmol) of HOBt, 0.83 ml (6.00 mmol) of triethylamine, WSC . HCl 575 mg (3.00 mmol) was sequentially added and stirred overnight at room temperature. The title compound was obtained by treating in a conventional manner using methylene chloride as an extraction solvent.
Yield 900 mg (2.05 mmol) Yield 75%
H-NMR (CDCl3) δ 2.50 (2H, br), 4.10 (2H, t), 5.05 (1H, q), 5.20 (1H, d), 5.28 (1H, d), 6.9-7.3 (4H, m ), 7.36 (5H, s), 7.72 (2H, d), 7.89 (2H, d)
Process 3
(2S) -2- (4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid Synthesis of ditrifluoroacetate
900 mg (2.05 mmol) of benzyl (2S) -2- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butanoate is added to 20 ml of ethanol (W / V) containing 30% hydrogen chloride, and And stirred overnight. Subsequently, after the solvent was distilled off under reduced pressure, it was dissolved in 20 ml of an ethanol solution containing 10% ammonia (w / v) at room temperature and stirred overnight at room temperature. The residue obtained by distilling off the solvent was dissolved in 10 ml of concentrated hydrochloric acid and stirred at 40 ° C. for 4 hours. The residue obtained by distilling off hydrogen chloride was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 364 mg (0.596 mmol) Yield 29%
MS (ESI, m / z) 384 (MH +)
H-NMR (DMSO-d6) δ 2.20 (2H, br), 4.20 (2H, br), 4.70 (1H, br), 7.30 (1H, d), 7.38 (1H, br), 7.93 (2H, d ), 8.08 (2H, d), 9.02 (1H, d), 9.20 (2H, s), 9.30 (2H, s), 9.34 (2H, s), 9.47 (2H, d).
Example 92
(2R) -2- (4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid Synthesis of ditrifluoroacetate
Process 1
Synthesis of (2R) -2-t-butoxycarbonylamino-4- (3-cyanophenoxy) butanoic acid benzyl
The title compound was obtained in the same manner as in Synthesis of Example 91, Step 1, using 5.0 g (15.0 mmol) of Nt-butoxycarbonyl-D-aspartic acid-α-benzyl ester as a starting material.
Yield 3.13 g (7.63 mmol) Yield 51%
H-NMR (CDCl3) δ1.40 (9H, s), 2.30 (2H, br), 4.05 (2H, t), 4.58 (1H, br), 5.20 (2H, t), 5.70 (1H, br), 7.0-7.2 (4H, m), 7.3 (5H, s)
Process 2
Synthesis of benzyl (2R) -2- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butanoate
(2R) -2-t-Butoxycarbonylamino-4- (3-cyanophenoxy) butanoic acid 3.13 g (7.63 mmol) as a starting material, the title compound was synthesized in the same manner as in Example 91, Step 2. Obtained.
Yield 2.19 g (6.62 mmol) Yield 87%
H-NMR (CDCl3) δ 2.50 (2H, br), 4.10 (2H, t), 5.05 (1H, q), 5.20 (1H, d), 5.28 (1H, d), 6.9-7.3 (4H, m ), 7.36 (5H, s), 7.72 (2H, d), 7.89 (2H, d)
Process 3
(2R) -2- (4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid Synthesis of ditrifluoroacetate
(2R) -2- (4-Cyanobenzoylamino) -4- (3-cyanophenoxy) butanoic acid benzyl 2.91 g (6.62 mmol) as a starting material in the same manner as the synthesis of Example 91, Step 3. The title compound was obtained.
Yield 895 mg (1.46 mmol) Yield 22%
MS (ESI, m / z) 384 (MH +)
H-NMR (DMSO-d6) δ 2.20 (2H, br), 4.20 (2H, br), 4.70 (1H, br), 7.30 (1H, d), 7.38 (1H, br), 7.93 (2H, d ), 8.08 (2H, d), 9.02 (1H, d), 9.20 (2H, s), 9.30 (2H, s), 9.34 (2H, s), 9.47 (2H, d).
Example 93
Measurement of activated blood coagulation factor X inhibitory activity
130 μl of 100 mM Tris-HCl buffer adjusted to pH 8.4 was added to 10 μl of the aqueous solution of the evaluation compound, and then human activated blood coagulation factor X (manufactured by Enzyme Research) was added to pH 8.4 Tris-HCl buffer. 10 μl of the solution prepared to 0.5 unit / ml was added and incubated at room temperature for 10 minutes. Next, N-benzoyl-L-isoleucyl-L-glutamyl-glycyl-L-arginyl-P-nitroanilide hydrochloride (manufactured by Peptide Institute, Inc.) was adjusted to 0.8 mM with pH 8.4 Tris-HCl buffer. 50 μl of the prepared solution was added, the absorbance was measured, and the initial reaction rate was determined. A control prepared by adding 10 μl of Tris-HCl buffer prepared to pH 8.4 instead of the solution of the evaluation compound was used as a control. The absorbance was measured using a Microplate Reader Model 3550-UV (manufactured by BIO RAD) at a wavelength of 405 nm for 16 minutes at 15 second intervals. The negative logarithmic value of the concentration of the evaluation compound when 50% of the activity (initial rate) of activated blood coagulation factor X when the evaluation compound is not added is inhibited (abbreviated as pIC50) is obtained. It was used as an index of factor inhibitory activity. Table 1 shows the activated blood coagulation factor X inhibitory activity of typical compounds.
Example 94
Measurement of thrombin inhibitory activity
130 μl of 100 mM Tris-HCl buffer solution adjusted to pH 8.4 is added to 10 μl of the aqueous solution of the evaluation compound, and then human thrombin (manufactured by SIGMA) is adjusted to 2 units / ml with pH 8.4 Tris-HCl buffer solution. 10 μl of the prepared solution was added and incubated at room temperature for 10 minutes. Subsequently, D-phenylalanyl-L-pipecolyl-L-arginyl-P-nitroanilide dihydrochloride (Daiichi Chemical Co., Ltd., S-2238) was adjusted to 0.4 mM with pH 8.4 Tris-HCl buffer. 50 μl of the prepared solution was added, the absorbance was measured, and the initial reaction rate was determined. A control prepared by adding 10 μl of Tris-HCl buffer prepared to pH 8.4 instead of the solution of the evaluation compound was used as a control. Absorbance was measured using a Microplate Reader Model 3550-UV (manufactured by BIO RAD) at a wavelength of 405 nm for 16 minutes at 15 second intervals. A negative logarithmic value of the concentration of the evaluation compound when 50% of the thrombin activity (initial rate) when the evaluation compound was not added was inhibited (abbreviated as pIC50) was used as an index of thrombin inhibition activity. Table 1 below shows the thrombin inhibitory activity of representative compounds.
Figure 0004103147
However, in the table, the compound of Example 83 represents (4S) -4- (4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoic acid ditrifluoroacetate.
This result shows that the benzamidine derivative of the present invention exhibits high inhibitory activity specific to activated blood coagulation factor X.
The structural formulas of the compounds of the present invention described in Examples are shown below.
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Example 95
N- [2- (3-Amidinophenoxy) ethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide was synthesized according to Steps 1 to 4 in Example 1.
Process 5
N- [2- (3-Amidinophenoxy) ethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
A solution of 2.43 g (8.35 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide in 56 ml of 4N hydrogen chloride in dioxane contains 30% hydrogen chloride (W / V) 24 ml of ethanol was added. After stirring at room temperature for 96 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 30 ml of an ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 24 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 1.19 g (2.15 mmol) Yield 26%
MS (FAB, m / z) 326 (MH +)
H-NMR (DMSO-d6) δ 3.69 (2H, dt), 4.24 (2H, t), 7.32 (1H, d), 7.39 (1H, d), 7.40 (1H, s), 7.53 (1H, t ), 7.90 (2H, d), 8.05 (2H, d), 9.02 (1H, t), 9.18 (2H, br), 9.30 (4H, br), 9.43 (2H, br)
Example 96
N- [2- (3-Amidinophenoxy) ethyl] -3-amidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -3-cyanobenzamide
The title compound was obtained in the same manner as in Step 4 of Example 1, using 162 mg (1.1 mmol) of 3-cyanobenzoic acid and 163 mg (1.0 mmol) of 3- (2-aminoethoxy) benzonitrile as starting materials.
Yield 251 mg (0.86 mmol) Yield 86%
H-NMR (CDCl3) δ 3.92 (2H, dt), 4.19 (2H, t), 6.67 (1H, br), 7.16 (1H, d), 7.18 (1H, s), 7.28 (1H, d), 7.40 (1H, t), 7.59 (1H, t), 7.80 (1H, t), 7.80 (1H, d), 8.03 (1H, d), 8.09 (1H, s)
Process 2
N- [2- (3-Amidinophenoxy) ethyl] -3-amidinobenzamide Synthesis of ditrifluoroacetate
The title compound was obtained in the same manner as step 5 of example 95, using 240 mg (0.82 mmol) of N- [2- (3-cyanophenoxy) ethyl] -3-cyanobenzamide as a starting material.
Yield 66.3 mg (0.12 mmol) Yield 14%
MS (FAB, m / z) 326 (MH +)
H-NMR (DMSO-d6) δ 3.70 (2H, dt), 4.25 (2H, t), 7.32 (1H, d), 7.41 (1H, d), 7.45 (1H, s), 7.51 (1H, t ), 7.71 (1H, t), 7.97 (1H, d), 8.18 (1H, d), 8.45 (1H, s), 8.92 (4H, br), 9.14 (1H, t)
Example 97
N- [2- (3-Amidinophenoxy) ethyl] -4- (4-piperidyloxy) benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of ethyl 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoate
Ethyl 4-hydroxybenzoate (1.7 g, 10.2 mmol), 1-t-butoxycarbonyl-4-hydroxypiperidine (1.76 g, 9.3 mmol), and triphenylphosphine (2.44 g, 9.3 mmol) were added to tetrahydrofuran (40 ml). After dissolution, 1.62 g (9.3 mmol) of diethyl azodicarboxylate was added at room temperature and stirred overnight. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.57 g (4.5 mmol) Yield 44%
H-NMR (CDCl3) δ 1.38 (3H, t), 1.50 (9H, s) 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 3.30-3.41 (2H, m), 3.63- 3.75 (2H, m), 4.35 (2H, q), 4.55 (1H, m), 6.90 (2H, d), 8.00 (2H, d)
Process 2
Synthesis of 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoic acid
847 mg (2.43 mmol) of ethyl 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoate was dissolved in 50 ml of ethanol, 5 ml of 1N sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated and ethyl acetate was used as an extraction solvent, and the mixture was treated according to the same isolation procedure as in Step 1 of Example 1 to obtain the title compound.
Yield 697 mg (2.2 mmol) Yield 92%
H-NMR (CDCl3) δ1.50 (9H, s), 1.70-2.00 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.60 (1H, s), 6.95 (2H, d), 8.05 (2H, d)
Process 3
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -4- (1-t-butoxycarbonyl-4-piperidyloxy) benzamide
Starting from 211.2 mg (0.65 mmol) of 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoic acid and 129.2 mg (0.65 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride The title compound was obtained in the same manner as in Step 4 of Example 1.
Yield 167 mg (0.36 mmol) Yield 55%
H-NMR (CDCl3) δ 1.50 (9H, s), 1.65-1.80 (2H, m), 1.85-2.00 (2H, m), 3.30-3.40. (2H, m), 3.60-3.75 (2H, m ), 3.90 (2H, dt), 4.20 (2H, t), 4.55 (1H, m), 6.45 (1H, t), 6.94 (2H, d), 7.15 (1H, d), 7.17 (1H, s) , 7.26 (1H, d), 7.38 (1H, t), 6.74 (2H, d)
Process 4
N- [2- (3-Amidinophenoxy) ethyl] -4- (4-piperidyloxy) benzamide Synthesis of ditrifluoroacetate
The same operation as in Step 3 of Example 1 starting from 165 mg (0.35 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4- (1-t-butoxycarbonyl-4-piperidyloxy) benzamide Was converted to N- [2- (3-cyanophenoxy) ethyl] -4- (4-piperidyloxy) benzamide, and the title compound was obtained in the same manner as in Step 5 of Example 95.
Yield 124 mg (0.20 mmol) Yield 57%
MS (ESI, m / z) 383 (MH +)
H-NMR (DMSO-d6) δ1.80-1.90 (2H, m), 2.08-2.18 (2H, m), 3.02-3.30 (4H, m), 3.62 (2H, q), 4.21 (2H, t) , 4.75 (1H, m), 7.06 (2H, d), 7.30-7.42 (3H, m), 7.53 (1H, t), 7.85 (2H, d), 8.58 (2H, br), 8.61 (1H, br ), 9.12 (2H, br), 9.28 (2H, br)
Example 98
N- [2- (3-Amidinophenoxy) ethyl] -4- (aminomethyl) benzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of ethyl 4- (aminomethyl) benzoate
4-aminomethylbenzoic acid 3 g (19.9 mmol) was suspended in ethanol 100 ml, ethanol 10 ml containing 25% hydrogen chloride was added, and the mixture was refluxed with heating for 8 hours. The title compound was obtained by evaporating the solvent and treating with ethyl acetate as the extraction solvent by the same isolation procedure as in Step 1 of Example 1.
Yield 1.19 g (6.77 mmol) Yield 34%
H-NMR (CDCl3) δ1.35 (3H, t), 4.05 (2H, brs), 4.30 (2H, q), 6.60 (2H, d), 7.85 (2H, d)
Process 2
Synthesis of ethyl 4-[(t-butoxycarbonylamino) methyl] benzoate
The title compound was obtained in the same manner as in Step 1 of Example 1, using ethyl 4- (aminomethyl) benzoate and di-t-butyldicarbonate as starting materials.
H-NMR (CDCl3) δ1.45 (9H, s), 4.36 (2H, d), 4.36 (2H, q), 4.90 (1H, br), 7.35 (2H, d), 8.00 (2H, d)
Process 3
Synthesis of 4-[(t-butoxycarbonylamino) methyl] benzoic acid
The title compound was obtained by the same procedures as in Step 2 of Example 97 using ethyl 4-[(t-butoxycarbonylamino) methyl] benzoate as a starting material.
H-NMR (CDCl3) δ1.43 (9H, s), 4.40 (2H, br), 4.95 (1H, br), 7.40 (2H, d), 8.10 (2H, d)
Process 4
N- [2- (3-Amidinophenoxy) ethyl] -4- (aminomethyl) benzamide Synthesis of ditrifluoroacetate
4-[(t-Butoxycarbonylamino) methyl] benzoic acid 439 mg (2 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 400 mg (2 mmol) were used as starting materials in the same manner as in Step 4 of Example 1. N- [2- (3-cyanophenoxy) ethyl] -4-[(t-butoxycarbonylamino) methyl] benzamide was used. This was converted to N- [2- (3-cyanophenoxy) ethyl] -4- (aminomethyl) benzamide hydrochloride according to the same procedure as in Step 3 of Example 1, then Step 5 of Example 95 and The title compound was obtained by the same operation.
MS (ESI, m / z) 313 (MH +)
H-NMR (DMSO-d6) δ 3.70 (2H, q), 4.10 (2H, s), 4.25 (2H, t), 7.30-7.40 (3H, m), 7.51-7.56 (3H, m), 7.91 (2H, d), 8.24 (3H, br), 8.78 (1H, t), 9.10 (2H, br), 9.27 (2H, br)
Example 99
N- [2- (3-Amidinophenoxy) ethyl] -4- (1-acetimidoyl-4-piperidyloxy) benzamide Synthesis of ditrifluoroacetate
N- [2- (3-amidinophenoxy) ethyl] -4- (4-piperidyloxy) benzamide 124 mg (0.2 mmol) of ditrifluoroacetate was dissolved in 5 ml of ethanol, 183 mg (1.8 mmol) of triethylamine, ethyl Acetimidate hydrochloride (147 mg, 1.2 mmol) was added, and the mixture was stirred at room temperature for 6 days. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 120 mg (0.18 mmol) Yield 92%
MS (ESI, m / z) 424 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.82 (2H, m), 2.02-2.14 (2H, m), 2.30 (3H, s), 3.50-3.60 (2H, m), 3.65 (2H, q) , 3.70-3.80 (2H, m), 4.20 (2H, t), 4.80 (1H, m), 7.07 (2H, d), 7.30-7.40 (3H, m), 7.53 (1H, t) 7.85 (2H, d) 8.57-8.63 (2H, m), 9.11-9.18 (3H, m), 9.28 (2H, br)
Example 100
N- [2- (3-Amidinophenoxy) ethyl]-(E) -3- (4-amidinophenyl) -2-propenamide Synthesis of ditrifluoroacetate
Process 1
(E) Synthesis of 3- (4-cyanophenyl) acrylic acid
4-Bromobenzonitrile (3.64 g, 20 mmol) and acrylic acid (2.88 g, 40 mmol) were dissolved in acetonitrile (40 ml), palladium (II) acetate (49 mg, 0.2 mmol), tri-o-tolylphosphine (365 mg, 1.2 mmol). ) And 7.41 g (40 mmol) of tributylamine were added and heated to reflux overnight. The reaction mixture was poured into 4N hydrogen chloride, and the resulting precipitate was collected by filtration, washed with 4N hydrogen chloride, water and ethyl acetate, and then dried in vacuo to give the title compound.
Yield 2.36 g (13.6 mmol) Yield 68%
H-NMR (DMSO-d6) δ 6.70 (1H, d), 7.65 (1H, d), 7.90 (4H, m)
Process 2
Synthesis of N- [2- (3-cyanophenoxy) ethyl]-(E) -3- (4-cyanophenyl) -2-propenamide
(E) -3- (4-Cyanophenyl) acrylic acid 173 mg (1 mmol), 3- (2-aminoethoxy) benzonitrile 146 mg (0.9 mmol) as starting materials, the same operation as in Step 4 of Example 1 Gave the title compound.
Yield 254 mg (0.8 mmol) Yield 89%
H-NMR (CDCl3) δ 3.82 (2H, q), 4.15 (2H, t), 6.10 (1H, br), 6.50 (1H, d), 7.15 (1H, d), 7.18 (1H, s), 7.25 (1H, d), 7.40 (1H, t), 7.60 (2H, d), 7.68 (1H, d), 7.70 (2H, d)
Process 3
N- [2- (3-Amidinophenoxy) ethyl]-(E) -3- (4-amidinophenyl) -2-propenamide Synthesis of ditrifluoroacetate
Similar to Step 5 of Example 95, starting from 254 mg (0.8 mmol) of N- [2- (3-cyanophenoxy) ethyl]-(E) -3- (4-cyanophenyl) -2-propenamide To give the title compound.
Yield 23 mg (0.04 mmol) Yield 5%
MS (ESI, m / z) 326 (MH +)
H-NMR (DMSO-d6) δ 3.60 (2H, q), 4.20 (2H, t), 6.85 (1H, d), 7.34 (1H, d), 7.38 (1H, s), 7.40 (1H, d ), 7.54 (1H, d), 7.55 (1H, t), 7.79 (2H, d), 7.85 (2H, d), 8.54 (1H, br), 9.18 (4H, br), 9.28 (2H, br) , 9.33 (2H, br)
Example 101
Synthesis of N- [3- (3-amidinophenoxy) ethyl] -4-[(Nt-butoxycarbonyl-N-methylamino) methyl] benzamide trifluoroacetate
Process 1
Synthesis of methyl 4- (Nt-butoxycarbonyl-N-methylamino) methylbenzoate
365 mg (1.45 mmol) of 4- (t-butoxycarbonylamino) methylbenzoic acid and 160 mg (4 mmol) of sodium hydride (oily, 60%) were dissolved in dimethylformamide, stirred at room temperature for 5 minutes, and then 1 ml of methyl iodide was added. The mixture was further stirred for 2 hours. Ethyl acetate was used as an extraction solvent, and the product was treated by the same isolation operation as in Step 1 of Example 1 to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 380 mg (1.36 mmol) Yield 94%
Process 2
Synthesis of 4- (Nt-butoxycarbonyl-N-methylamino) methylbenzoic acid
The title compound was obtained in the same manner as in step 2 of Example 97, using 370 mg (1.3 mmol) of methyl 4- (Nt-butoxycarbonyl-N-methylamino) methylbenzoate as a starting material.
Yield 330 mg (1.24 mmol) Yield 95%
Process 3
Synthesis of N- [3- (3-amidinophenoxy) ethyl] -4-[(Nt-butoxycarbonyl-N-methylamino) methyl] benzamide trifluoroacetate
Starting from 330 mg (1.24 mmol) of 4- (Nt-butoxycarbonyl-N-methylamino) methylbenzoic acid and 313 mg (1.24 mmol) of 3- (2-aminoethoxy) benzamidine dihydrochloride as starting materials, Examples In the same manner as in Step 5 of 124, condensation and purification by reverse phase high performance liquid chromatography were performed to obtain the title compound.
Yield 155 mg (0.237 mmol) Yield 20%
MS (ESI, m / z) 427 (MH +)
Example 102
Synthesis of N- [3- (3-amidinophenoxy) ethyl] -4-[(methylamino) methyl] benzamide ditrifluoroacetate
N- [3- (3-Amidinophenoxy) ethyl] -4-[(Nt-butoxycarbonyl-N-methylamino) methyl] benzamide trifluoroacetic acid salt 140 mg (0.26 mmol) was dissolved in trifluoroacetic acid. And stirred at room temperature for 30 minutes. Subsequently, trifluoroacetic acid was distilled off to obtain the title compound.
Yield 133 mg (0.24 mmol) Yield 92%
MS (ESI, m / z) 411 (MH + + DMSO-d6)
Example 103
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- [1-t-butoxycarbonyl- (3S) -3-pyrrolidyloxy] phenylacetamide trifluoroacetate
Process 1
Synthesis of (3R) -1- (t-butoxycarbonyl) -3-hydroxy-pyrrolidine
2-4-g (191 mmol) of trans-4-hydroxy-L-proline and 1.5 ml of cyclohexanone were dissolved in 150 ml of cyclohexanol and stirred at 160 ° C. for 16 hours. Dilution with methyl isobutyl ketone was performed, and a 1N hydrochloric acid aqueous solution was used as an extraction solvent, and a crude product was obtained by the same isolation operation as in Step 1 of Example 1. The oily residue thus obtained was dissolved in 300 ml of tetrahydrofuran and 300 ml of water, 34 ml (244 mmol) of triethylamine and 31.4 g (143 mmol) of di-t-butyl dicarbonate were added at 0 ° C. and stirred for 4 hours. Ethyl acetate was used as an extraction solvent, and the product was treated by the same isolation operation as in Step 1 of Example 1 to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 27.4 g (146 mmol) Yield 76%
MS (FAB, m / z) 188 (MH +)
H-NMR (CDCl3) δ1.46 (9H, s), 2.25-2.31 (2H, m) 3.20-3.57 (4H, m), 4.42 (1H, s), 4.74 (1H, s)
Process 2
Synthesis of ethyl 2- [4-[(3S) -1- (t-butoxycarbonyl) -3-pyrrolidyloxy] phenyl] acetate
4-hydroxyphenyl acetate ethyl ester 6.0g (33.3mmol), (3R) -1- (t-butoxycarbonyl) -3-hydroxy-pyrrolidine 6.25g (33.3mmol), triphenylphosphine 10.5g ( 40 mmol) was dissolved in 125 ml of tetrahydrofuran, and 6.3 ml (40 mmol) of diethyl azodicarboxylate was added at room temperature, followed by stirring for 42 hours. Ethyl acetate was used as an extraction solvent, and the product was treated by the same isolation operation as in Step 1 of Example 1 to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 5.7 g (16.3 mmol) Yield 49%
MS (FAB, m / z) 349 (MH +)
H-NMR (CDCl3) δ1.24 (3H, t), 1.46 (9H, s), 2.05-2.20 (2H, m), 3.50 (2H, s), 3.40-3.62 (4H, m), 4.15 (2H , q), 4.85 (1H, s), 6.81 (1H, d), 6.83 (1H, d), 7.19 (1H, d), 7.23 (1H, d)
Process 3
Synthesis of 2- [4-[(3S) -1-t-butoxycarbonyl-3-pyrrolidyloxy] phenyl] acetic acid
750 mg of ethyl 2- [4-[(3S) -1- (t-butoxycarbonyl) -3-pyrrolidyloxy] phenyl] acetate was dissolved in 10 ml of ethanol, and 4 ml of 1N aqueous sodium hydroxide solution was added. After stirring overnight at room temperature, the solvent was distilled off. 1N Hydrochloric acid was added, and ethyl acetate was used as an extraction solvent. The title compound was obtained by the same isolation procedures as in Step 1 of Example 1.
Yield 830mg
H-NMR (CDCl3) δ1.45 (9H, s), 2.00-2.20 (2H, m), 3.42-3.62 (6H, m), 3.85 (1H, brs), 6.80 (2H, d), 7.20 (2H , d)
Process 4
Synthesis of 4- [1-t-butoxycarbonyl- (3S) -3-pyrrolidyloxy] phenylacetic acid
The title compound was obtained by the same procedures as in Step 2 of Example 97 using ethyl 4- [1-t-butoxycarbonyl- (3S) -3-pyrrolidyloxy] phenyl acetate as a starting material.
Process 5
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- [1-t-butoxycarbonyl- (3S) -3-pyrrolidyloxy] phenylacetamide trifluoroacetate
4- [1-t-Butoxycarbonyl- (3S) -3-pyrrolidyloxy] phenylacetic acid, 3- (2-aminoethoxy) benzamidine dihydrochloride as starting materials and condensation as in Step 5 of Example 124 Reaction and purification by reverse phase high performance liquid chromatography gave the title compound.
MS (ESI, m / z) 483 (MH +)
H-NMR (DMSO-d6) δ 1.40 (9H, s), 1.95-2.15 (2H, m), 3.25-3.55 (8H, m), 4.10 (2H, t), 4.90 (1H, brs), 6.84 (2H, d), 7.17 (2H, d), 7.30 (1H, d), 7.36 (1H, s), 7.38 (1H, d), 7.53 (1H, t), 8.26 (1H, brt), 9.04 ( 2H, brs), 9.28 (2H, brs)
Example 104
N- [2- (3-Amidinophenoxy) ethyl] -4-[(3S) -3-pyrrolidyloxy] phenylacetamide Synthesis of ditrifluoroacetate
N- [2- (3-amidinophenoxy) ethyl] -4- [1-t-butoxycarbonyl- (3S) -3-pyrrolidyloxy] phenylacetamide trifluoroacetate dissolved in 4N hydrogen chloride in dioxane And stirred at room temperature for 1 hour. After distilling off the solvent, the obtained residue was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
MS (ESI, m / z) 383 (MH +)
H-NMR (DMSO-d6) δ 2.05-2.25 (2H, m), 3.20-3.60 (8H, m), 4.10 (2H, t), 7.08 (2H, d), 7.20 (2H, d), 7.30 (1H, d), 7.40 (1H, d), 7.38 (1H, s), 7.54 (1H, t), 8.36 (1H, brt), 9.19 (2H, brs), 9.31 (2H, brs), 9.33 ( 2H, brs)
Example 105
Synthesis of N- [2- (3-amidinophenoxy) ethyl]-(1-acetyl-4-piperidine) carboxamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl]-(1-acetyl-4-piperidine) carboxamide
Starting from 175 mg (1.02 mmol) of 1-acetyl-4-piperidinecarboxylic acid and 150 mg (0.92 mmol) of 3- (2-aminoethoxy) benzonitrile, the title compound was prepared in the same manner as in Step 4 of Example 1. Obtained.
Yield 84.4 mg (0.27 mmol) Yield 29%
H-NMR (CDCl3) δ 1.60-1.77 (2H, m), 1.82-1.93 (2H, m), 2.10 (3H, s), 2.35 (1H, m), 2.65 (1H, m), 3.09 (1H , m), 3.69 (2H, dt), 3.87 (1H, m), 4.06 (2H, t), 4.60 (1H, m), 5.97 (1H, br), 7.12 (1H, d), 7.14 (1H, s), 7.27 (1H, d), 7.40 (m, t)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl]-(1-acetyl-4-piperidine) carboxamide trifluoroacetate
The title compound was obtained in the same manner as in Step 5 of Example 95 using 75 mg (0.24 mmol) of N- [2- (3-cyanophenoxy) ethyl]-(1-acetyl-4-piperidine) carboxamide as a starting material. It was.
Yield 12.3 mg (0.028 mmol) Yield 12%
MS (ESI, m / z) 333 (MH +)
H-NMR (CD3OD) δ1.43-1.82 (4H, m), 2.15 (3H, s), 2.50 (1H, m), 2.65 (1H, m), 3.15 (1H, m), 3.60 (2H), 3.95 (1H, m), 4.15 (2H, t), 4.50 (1H, m), 7.31 (1H, d), 7.35 (1H, s), 7.37 (1H, d) 7.52 (1H, t)
Example 106 Synthesis of N- [2- (3-amidinophenoxy) ethyl]-(1S) -10-camphorsulfonamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl]-(1S) -10-camphorsulfonamide
700 mg (4.32 mmol) of 3- (2-aminoethoxy) benzonitrile was dissolved in 20 ml of DMF, 0.75 ml (4.32 mmol) of diisopropylethylamine, and (1S)-(+)-10-camphorsulfonyl dissolved in 5 ml of DMF. 1.08 g (4.32 mmol) of chloride was added at 0 ° C. and stirred for 4 hours. Ethyl acetate was used as an extraction solvent, and the product was treated by the same isolation operation as in Step 1 of Example 1 to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.41 g (3.75 mmol) Yield 87%
MS (ESI, m / z) 377 (MH +)
H-NMR (CDCl3) δ0.88 (3H, s), 1.04 (3H, s), 1.47 (1H, ddd), 1.89-2.15 (5H, m), 2.33 (1H, td), 2.98 (1H, d ), 3.46 (1H, d), 3.59 (2H, dt), 4.14 (2H, t), 6.00 (1H, t), 7.15 (1H, d), 7.18 (1H, s), 7.26 (1H, d) , 7.39 (1H, t)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl]-(1S) -10-camphorsulfonamide trifluoroacetate
Starting from 1.41 g (3.75 mmol) of N- [2- (3-cyanophenoxy) ethyl]-(1S) -10-camphorsulfonamide, the title compound was obtained in the same manner as in Step 5 of Example 95. Obtained.
Yield 342 mg (0.67 mmol) Yield 18%
MS (ESI, m / z) 394 (MH +)
H-NMR (DMSO-d6) δ 0.86 (3H, s), 0.93 (3H, s), 1,38 (1H, ddd), 1.78-1.91 (2H, m), 2.17-2.21 (2H, m) , 2.52 (1H, d), 2.56 (1H, d), 3.05-3.30 (2H, m), 4.00-4.05 (2H, m), 4.37 (2H, t), 7.34 (1H, d), 7.40 (1H , s), 7.45 (1H, d), 7.55 (1H, q), 9.13 (2H, s), 9.31 (2H, s)
Example 107
Synthesis of N- [2- (3-amidinophenoxy) ethyl]-(1R) -10-camphorsulfonamide trifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl]-(1R) -10-camphorsulfonamide
Using 700 mg (4.32 mmol) of 3- (2-aminoethoxy) benzonitrile and 1.08 g (4.32 mmol) of (1R)-(−)-10-camphorsulfonyl chloride as starting materials, Step 1 of Example 106 and The title compound was obtained according to the same procedure.
Yield 1.33 g (3.54 mmol) Yield 82%
MS (ESI, m / z) 377 (MH +)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl]-(1R) -10-camphorsulfonamide trifluoroacetate
Starting from 1.33 g (3.54 mmol) of N- [2- (3-cyanophenoxy) ethyl]-(1R) -10-camphorsulfonamide, the title compound was prepared in the same manner as in Step 5 of Example 95. Obtained.
Yield 320 mg (0.63 mmol) Yield 18%
MS (ESI, m / z) 394 (MH +)
H-NMR (DMSO-d6) δ 0.86 (3H, s), 0.93 (3H, s), 1,35 (1H, ddd), 1.78-1.91 (2H, m), 2.12-2.21 (2H, m) , 2.59 (1H, d), 2.76 (1H, d), 3.11 (1H, d), 3.14 (1H, d), 4.08 (2H, br), 4.37 (2H, br), 7.33 (1H, dd), 7.40 (1H, s), 7.42 (1H, d), 7.56 (1H, t), 7.55 (1H, q), 9.11 (2H, s), 9.31 (2H, s)
Example 108
Synthesis of 1- [2- (3-amidinophenoxy) ethylcarbamoyl] methyl] quinuclidinium ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] bromoacetamide
3- (2-aminoethoxy) benzonitrile (1.50 g, 9.26 mmol) and diisopropylethylamine (1.77 ml, 10.2 mmol) were dissolved in tetrahydrofuran (15 ml), and bromoacetyl chloride (0.92 ml, 11.1 ml) dissolved in tetrahydrofuran (5 ml). 1 mmol) was added at 0 ° C. and stirred for 8 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 2.18 g (7.73 mmol) Yield 83%
MS (ESI, m / z) 305 (M + Na +)
H-NMR (CDCl3) δ 3.76 (2H, dt), 3.98 (2H, d), 4.08 (2H, t), 7.14 (1H, dd), 7.16 (1H, s), 7.28 (1H, dd), 7.39 (1H, td)
Process 2
Synthesis of [1- [2- (3-amidinophenoxy) ethylcarbamoyl] methyl] quinuclidinium ditrifluoroacetate
N- [2- (3-cyanophenoxy) ethyl] bromoacetamide 500 mg (1.77 mmol) and quinuclidine 196 mg (1.77 mmol) were dissolved in chloroform 5 ml and stirred at 100 ° C. for 2 hours and further at room temperature for 15 hours. The solvent was distilled off to obtain an oily residue. The oily residue thus obtained was treated in the same manner as in step 5 of Example 95 to give the title compound.
Yield 258 mg (0.46 mmol) Yield 26%
MS (ESI, m / z) 331 (M +)
H-NMR (DMSO-d6) δ1.88 (6H, m), 2.07 (1H, br), 3.58 (8H, m), 3.95 (2H, s), 4.14 (2H, t), 7.29 (1H, dd ), 7.39 (1H, s), 7.43 (1H, d), 7.53 (1H, t), 9.02 (1H, t), 9.34 (2H, s), 9.55 (2H, s)
Example 109
N- [2- (3-Amidinophenoxy) ethyl]-(3-quinuclidinyl) aminoacetamide Synthesis of tritrifluoroacetate
N- [2- (3-cyanophenoxy) ethyl] -bromoacetamide 500 mg (1.77 mmol), 3-aminoquinuclidine hydrochloride 423 mg (2.13 mmol), potassium carbonate 586 mg (4.25 mmol), potassium iodide 323 mg (1.95 mmol) was dissolved in 5 ml of DMF and stirred at 0 ° C. for 105 minutes and further at room temperature for 6 hours. The residue obtained by distilling off the solvent under reduced pressure was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). Elution was performed with a mixed solvent of water and acetonitrile, and a fraction of the target product was lyophilized to obtain a crystalline substance. The crystalline material thus obtained was treated in the same manner as in Step 5 of Example 95 to obtain the title compound.
Yield 80 mg (0.12 mmol) Yield 6.8%
MS (ESI, m / z) 346 (MH +)
H-NMR (DMSO-d6) δ1.91-2.03 (4H, m), 2.28-2.38 (1H, m), 3.10-3.40 (5H, m), 3.55 (2H, dd), 3.70-3.83 (2H, m), 4.08 (2H, t), 4,15 (2H, m), 7.27 (1H, s), 7.32 (1H, d), 7.46 (1H, d), 7.54 (1H, t), 9.23 (2H , br), 9.46 (2H, br)
Example 110
Synthesis of 3- [2- (2-naphthalenesulfonylamino) ethoxy] benzamidine trifluoroacetate
Process 1
Synthesis of 3- [2- (2-naphthalenesulfonylamino) ethoxy] benzonitrile
163 mg of 3- (2-aminoethoxy) benzonitrile and 0.5 ml of diisopropylethylamine were dissolved in 10 ml of dimethylformamide, 250 mg (1.1 mmol) of 2-naphthalenesulfonyl chloride dissolved in dimethylformamide was added under ice cooling, and the mixture was cooled under ice cooling. Stir for 2 hours. The title compound was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent.
Yield 320 mg (0.91 mmol) Yield 91%
H-NMR (CDCl3) δ3.45 (2H, dt), 4.00 (2H, t), 5.05 (1H, br), 6.96 (1H, s), 6.97 (1H, d), 7.20 (1H, d), 7.30 (1H, t), 7.59-7.70 (2H, m), 7.82-7.98 (4H, m), 8.46 (1H, s)
Process 2
Synthesis of 3- [2- (2-naphthalenesulfonylamino) ethoxy] benzamidine trifluoroacetate
The title compound was obtained in the same manner as step 5 of example 95, using 300 mg (0.85 mol) of 3- [2- (2-naphthalenesulfonylamino) ethoxy] benzonitrile as a starting material.
Yield 168 mg (0.35 mmol) Yield 41%
MS (FAB, m / z) 384 (MH +)
H-NMR (DMSO-d6) δ3.20 (2H, br), 4.10 (2H, br), 7.14 (1H, d), 7.22 (1H, s), 7.33 (1H, d), 7.44 (1H, t ), 7.60-8.20 (7H, m), 8.41 (1H, s), 9.10 (4H, br)
Example 111
Synthesis of 3- [2- (4-Amidinobenzenesulfonylamino) ethoxy] benzamidine ditrifluoroacetate
Process 1
Synthesis of 3- [2- (4-Bromobenzenesulfonylamino) ethoxy] benzonitrile
Using 460 mg (1.8 mmol) of 4-bromobenzenesulfonyl chloride and 294 mg (1.8 mmol) of 3- (2-aminoethoxy) benzonitrile as starting materials, the title compound was obtained in the same manner as in Step 1 of Example 110. .
Yield 604 mg (1.7 mmol) Yield 94%
H-NMR (CDCl3) δ3.40 (2H, dt), 4.02 (2H, t), 5.00 (1H, br), 7.03 (1H, d), 7.50 (1H, s), 7.27 (1H, d), 7.37 (1H, t), 7.65 (2H, d), 7.75 (2H, d)
Process 2
Synthesis of 3- [2- (4-cyanobenzenesulfonylamino) ethoxy] benzonitrile
3- [2- (4-Bromobenzenesulfonylamino) ethoxy] benzonitrile 300 mg (0.84 mmol) was dissolved in 1 ml of N-methylpyrrolidone, and 76 mg (0.84 mmol) of copper (I) cyanide was added at 140 ° C. Stir overnight. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 45 mg (0.14 mmol) Yield 16%
MS (ESI, m / z) 350 (MNa +)
H-NMR (CDCl3) δ3.25 (2H, dt), 4.05 (2H, t), 5.15 (1H, br), 7.40 (1H, d), 7.50 (1H, s), 7.28 (1H, d), 7.38 (1H, t), 7.82 (2H, d), 8.01 (2H, d)
At the same time, 4- [2- (3-cyanophenoxy) ethylsulfamoyl] benzamide was obtained.
Yield 21 mg (0.06 mmol) Yield 7%
H-NMR (CD3OD) δ3.35 (2H, t), 4.00 (2H, t), 7.10 (1H, d), 7.15 (1H, s), 7.39 (1H, t), 7.92-8.01 (4H, m )
Process 3
Synthesis of 3- [2- (4-Amidinobenzenesulfonylamino) ethoxy] benzamidine ditrifluoroacetate
The title compound was obtained by the same procedures as in Step 5 of Example 95, using 40 mg (0.14 mmol) of 3- [2- (4-cyanobenzenesulfonylamino) ethoxy] benzonitrile as a starting material.
Yield 9.0 mg (0.015 mmol) Yield 11%
MS (ESI, m / z) 362 (MH +)
H-NMR (DMSO-d6) δ3.20 (2H, dt), 4.10 (2H, t), 7.21 (1H, d), 7.33 (1H, s), 7.40 (1H, d), 7.51 (1H, t ), 7.98-8.05 (4H, m), 8.41 (1H, br) 9.25 (2H, br), 9.30 (2H, br), 9.48 (4H, br)
Example 112
Synthesis of 4- [2- (3-Amidinophenoxy) ethylsulfamoyl] benzamide trifluoroacetate
The title compound was obtained by the same procedures as in Step 5 of Example 95, using 20 mg (0.058 mmol) of 4- [2- (3-cyanophenoxy) ethylsulfamoyl] benzamide as a starting material.
Yield 5 mg (0.010 mmol) Yield 17%
MS (ESI, m / z) 363 (MH +)
H-NMR (DMSO-d6) δ3.20 (2H, dt), 4.05 (2H, q), 7.20 (1H, d), 7.31 (1H, s), 7.37 (1H, d), 7.50 (1H, t ), 7.59 (1H, br), 7.89 (2H, d), 8.02 (2H, d), 8.10 (1H, br), 8.14 (1H, br), 9.05 (2H, br), 9.30 (2H, br)
Example 113
Synthesis of 3- [2- (4-Bromobenzenesulfonylamino) ethoxy] benzamidine trifluoroacetate
The title compound was obtained by the same procedures as in Step 5, Example 95, using 40 mg (0.11 mmol) of 3- [2- (4-bromobenzenesulfonylamino) ethoxy] benzonitrile as a starting material.
Yield 26 mg (0.04 mmol) Yield 36%
MS (ESI, m / z) 398 (MH +), 400 ((M + 2) H +)
H-NMR (DMSO-d6) δ3.20 (2H, dt), 4.05 (2H, t), 7.20 (1H, d), 7.28 (1H, s), 7.38 (1H, d), 7.51 (1H, t ), 7.73-7.82 (4H, m), 8.10 (1H, br), 9.10 (2H, br), 9.28 (2H, br)
Example 114
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -N-phenylmethyl-4-amidinobenzamide ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -N-phenylmethyl-4-cyanobenzamide
Sodium hydride (oil 60%) 28 mg (0.7 mmol) was stirred in dimethylformamide under ice cooling. 200 mg (0.69 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide was dissolved in a small amount of dimethylformamide and added. After the generation of hydrogen was completed, 257 mg (1.5 mmol) of benzyl bromide was added and then stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, 1N hydrogen chloride was added and ethyl acetate was used as an extraction solvent, and the title compound was obtained by the same isolation operation as in Step 1 of Example 1.
Yield 315 mg (0.83 mmol) Yield> 100%
Rotational isomers A and B of H-NMR (CDCl3) amide 1: 3 mixture δ 3.30 (2H, brs, A), 3.85 (2H, brs, B), 3.85 (2H, brs, A), 4.25 ( 2H, brs, B), 4.61 (2H, brs, B), 4.85 (2H, brs, A), 6.90-7.75 (13H, m)
Process 2
N- [2- (3-Amidinophenoxy) ethyl] -N-phenylmethyl-4-amidinobenzamide ditrifluoroacetate
The title compound was obtained in the same manner as the process 5 of Example 95 using 300 mg (0.79 mmol) of N- [2- (3-cyanophenoxy) ethyl] -N-phenylmethyl-4-cyanobenzamide.
Yield 152 mg (0.24 mmol) Yield 30%
MS (ESI, m / z) 416 (MH +)
1: 1 mixture of rotational isomers A and B of H-NMR (DMSO-d6) amide δ3.55 (2H, brs, A or B), 3.75 (2H, brs, A or B), 4.10 (2H, brs , A or B), 4.30 (2H, brs, A or B), 4.60 (2H, brs, A or B), 4.80 (2H, brs, A or B), 7.20-7.95 (13H, m), 9.20- 9.50 (8H, m)
Example 115
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -N-methyl-4-amidinobenzamide ditrifluoroacetate
Process 1
Synthesis of N- [2- (3-cyanophenoxy) ethyl] -N-methyl-4-cyanobenzamide 200 mg (0.69 mmol) of N- [2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide, iodine The title compound was obtained in the same manner as in Step 1 of Example 114 using 500 mg (excess amount) of methyl chloride as a starting material.
Yield 221 mg (0.73 mmol) Yield> 100%
Rotational isomers A and B of H-NMR (CDCl3) amide 1: 3 mixture δ3.15 (3H, brs, B), 3.20 (3H, brs, A), 3.70 (2H, brs, A), 3.95 ( 2H, brs, B), 4.05 (2H, brs, A), 4.30 (2H, brs, B), 7.04-7.20 (2H, m), 7.28 (1H, d), 7.40 (1H, t), 7.49- 7.59 (2H, m), 7.72 (2H, d)
Process 2
Synthesis of N- [2- (3-amidinophenoxy) ethyl] -N-methyl-4-amidinobenzamide ditrifluoroacetate
The title compound was obtained in the same manner as in Step 5 of Example 95, using 200 mg (0.66 mmol) of N- [2- (3-cyanophenoxy) ethyl] -N-methyl-4-cyanobenzamide as a starting material.
Yield 130 mg (0.23 mmol) Yield 35%
MS (ESI, m / z): 340 (MH +)
1: 1 mixture of rotamers A and B of H-NMR (DMSO-d6) amide δ3.00 (3H, s, A or B), 3.05 (3H, s, A or B), 3.62 (2H, s , A or B), 3.90 (2H, s, A or B), 4.15 (2H, s, A or B), 4.35 (2H, s, A or B), 7.22-7.70 (6H, m), 7.90 ( 2H, d), 9.18-9.42 (8H, m)
Example 116
N-[(1S) -2- (3-amidinophenoxy) -1-benzylethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N-[(1S) -1-benzyl-2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide
L-Phenylalanine methyl ester hydrochloride 4.5 g (20.9 mmol) was used as a starting material, and the same operation as in Example 117, Step 1 was performed without purifying the intermediate to obtain a crude product. Purification by silica gel column chromatography yielded the title compound.
Yield 1.03 g (2.70 mmol) Yield 12.9%
MS (ESI, m / z) 489 (MH +)
H-NMR (CDCl3) δ3.15 (2H, d), 4.01-4.18 (2H, m), 4.63-4.80 (1H, m), 6.67 (1H, d), 7.15-7.42 (9H, m), 7.67 (2H, d), 7.81 (2H, d)
Process 2
N-[(1S) -2- (3-amidinophenoxy) -1-benzylethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
The title compound was obtained in the same manner as the step 2 in Example 117 using 1.03 g (2.70 mmol) of N-[(1S) -1-benzyl-2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide. It was.
Yield 305 mg (0.474 mmol) Yield 17.6%
MS (ESI, m / z) 416 (MH +)
H-NMR (DMSO-d6) δ 2.95-3.17 (2H, m), 4.12-4.27 (2H, m), 4.55-4.62 (1H, m), 7.17-7.85 (2H, d), 7.97 (2H, d), 8.80 (1H, d), 9.24 (2H, br), 9.30 (2H, br), 9.42 (4H, br)
Example 117
N-[(1R) -2- (3-amidinophenoxy) -1-benzylethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N-[(1R) -1-benzyl-2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide
D-Phenylalanine methyl ester hydrochloride 4.5 g (20.9 mmol) as a starting material The same as steps 2, 4, 5, 6 of Example 150, steps 3 and 4 of Example 1 without purification of the intermediate The operation was sequentially performed to obtain a crude product. Purification by silica gel column chromatography yielded the title compound.
Yield 0.95 g (2.49 mmol) Yield 11.9%
MS (ESI, m / z) (MH +)
H-NMR (CDCl3) δ 3.17 (2H, d), 4.01-4.17 (2H, m), 4.67-4.80 (1H, m), 6.38 (1H, d), 7.08-7.42 (9H, m), 7.75 (2H, d), 7.82 (2H, d)
Process 2
N-[(1R) -2- (3-amidinophenoxy) -1-benzylethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Perform the same operation as in Step 7 of Example 150 using 0.95 g (2.49 mmol) of N-[(1R) -1-benzyl-2- (3-cyanophenoxy) ethyl] -4-cyanobenzamide to obtain the title compound. Obtained.
Yield 188 mg (0.474 mmol) Yield 17.6%
MS (ESI, m / z) 416 (MH +)
H-NMR (DMSO-d6) δ 2.95-3.18 (2H, m), 4.17-4.27 (2H, m), 4.52-4.62 (1H, m), 7.19-7.57 (9H, m), 7.85 (2H, d), 7.98 (2H, d), 8.79 (1H, d), 9.24 (2H, br), 9.32 (2H, br), 9.42 (4H, br)
Example 118
Synthesis of ethyl (3R) -3- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butanoate ditrifluoroacetate
Process 1
Synthesis of benzyl (3R) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butanoate
Nt-butoxycarbonyl-D-aspartic acid-β-benzyl ester 3.23 g (10.0 mmol) and triethylamine 1.39 ml (10.0 mmol) were dissolved in tetrahydrofuran 50 ml, and ice-cooled ethyl chloroformate 0.96 ml (10.0 mmol) was added and stirred for 20 minutes. The generated precipitate was removed by suction filtration, and 5 g of ice and 0.76 g (20.0 mmol) of sodium borohydride were added to the filtrate under ice cooling and stirred for 1.5 hours. 20 ml of 1N aqueous hydrogen chloride solution was added thereto, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. The oily residue thus obtained was dissolved in 36 ml of tetrahydrofuran, 0.96 g (8.04 mmol) of 3-cyanophenol, 2.30 g (8.77 mmol) of triphenylphosphine, diethyl azodicarboxylate (40% toluene solution). 50 g (8.04 mmol) was added and stirred overnight at room temperature. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 1.80 g (4.38 mmol) Yield 44%
H-NMR (CDCl3) δ 1.46 (9H, s), 2.79 (2H, d), 4.00 (1H, dd), 4.06 (1H, dd), 4.41 (1H, br), 5.13 (2H, s), 5.56 (1H, br), 7.05-7.18 (4H, m), 7.21-7.38 (5H, m)
Process 2
Synthesis of benzyl (3R) -3- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butanoate
1.8 g (4.38 mmol) of benzyl (3R) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butanoate is dissolved in 20 ml of 4N hydrogen chloride in dioxane and stirred at 0 ° C. for 6 hours. did. The oily residue obtained by distilling off the solvent was dissolved in 5 ml of dichloromethane, and 1.09 g (6.58 mmol) of 4-cyanobenzoic acid chloride and 1.22 ml (8.76 mmol) of triethylamine were added under ice-cooling. Stir overnight. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.21 g (2.75 mmol) Yield 63%
H-NMR (CDCl3) δ 2.86 (1H, dd), 2.95 (1H, dd), 4.12 (1H, dd), 4.20 (1H, dd), 4.85 (1H, br), 5.16 (2H, s), 7.09 (1H, d), 7.11 (1H, dd), 7.24-7.40 (7H, m), 7.72 (2H, d), 7.83 (2H, d)
Process 3
Synthesis of ethyl (3R) -3- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butanoate ditrifluoroacetate
1.21 g (2.75 mmol) of benzyl (3R) -3- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butanoate is added to 20 ml of ethanol containing 30% hydrogen chloride (W / V). Stir at room temperature overnight. Subsequently, the mixture was dissolved in 30 ml of an ethanol solution containing 10% ammonia (w / v) at room temperature and stirred overnight at room temperature. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 0.456 mg (0.713 mmol) Yield 25.9%
MS (ESI, m / z) 412 (MH +)
H-NMR (DMSO-d6) δ 1.15 (3H, t), 2.82 (2H, d), 4.07 (2H, q), 4.12 (1H, dd), 4.24 (1H, dd), 4.72 (1H, br ), 7.33 (1H, d), 7.39 (1H, s), 7.40 (1H, d), 7.54 (1H, dd), 7.91 (2H, d), 8.02 (2H, d), 8.84 (1H, d) , 9.16 (2H, s), 9.28 (4H, s), 9.42 (2H, s)
Example 119
(3R) -3- (4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid Synthesis of ditrifluoroacetate
(3R) -3- (4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid 0.466 g (0.729 mmol) of ditrifluoroacetate was dissolved in 10 ml of concentrated hydrochloric acid and dissolved at 40 ° C. for 6 hours. Stir. The residue obtained by distilling off hydrogen chloride was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 0.151 mg (0.247 mmol) Yield 46%
MS (ESI, m / z) 384 (MH +)
H-NMR (DMSO-d6) δ 2.74 (2H, d), 4.13 (1H, dd), 4.24 (1H, dd), 4.69 (1H, ddt), 7.35 (1H, d), 7.40 (1H, d ), 7.41 (1H, s), 7.55 (1H, dd), 7.91 (2H, d), 8.03 (2H, d), 8.81 (1H, d), 9.20 (2H, s), 9.28 (2H, s) , 9.33 (2H, s), 9.43 (2H, s)
Example 120
Synthesis of ethyl (4R) -4- (4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoate ditrifluoroacetate
Process 1
Synthesis of (4R) -4-t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoic acid benzyl
Starting from 3.37 g (10.0 mmol) of Nt-butoxycarbonyl-D-glutamic acid-γ-benzyl ester as starting material, benzyl (3R) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butanoate The title compound was obtained in the same manner as in the synthesis of.
Yield 3.20 g (7.54 mmol) Yield 75.4%
H-NMR (CDCl3) δ 1.44 (9H, s), 1.69 (2H, br), 2.02 (2H, br), 3.98 (2H, br), 4.83 (1H, br), 5.11 (2H, s), 7.04-7.16 (4H, m), 7.24-7.40 (5H, m)
Process 2
Synthesis of (4R) -4- (4-cyanobenzoylamino) -5- (3-cyanophenoxy) pentanoic acid benzyl
Starting from 3.20 g (7.54 mmol) of benzyl (4R) -4-t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoate, (3R) -3- (4-cyanobenzoylamino)- The title compound was obtained in the same manner as in the synthesis of benzyl 4- (3-cyanophenoxy) butanoate.
Yield 2.16 g (4.76 mmol) Yield 63.2%
H-NMR (CDCl3) δ 2.10-2.28 (2H, m), 2,54 (1H, ddd), 2.69 (1H, ddd), 4.10 (1H, dd), 4.18 (1H, dd), 4.48 (1H , br), 5.12 (2H, s), 7.00 (1H, br), 7.14-7.19 (2H, m), 7.24-7.41 (7H, m), 7.72 (2H, d), 7.87 (2H, d)
Process 3
Synthesis of ethyl (4R) -4- (4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoate ditrifluoroacetate
Starting from 2.16 g (4.76 mmol) of benzyl (4R) -4- (4-cyanobenzoylamino) -5- (3-cyanophenoxy) pentanoate, (3R) -3- (4-amidinobenzoylamino) ) -4- (3-Amidinophenoxy) butanoic acid ethyl The title compound was obtained in the same manner as in the synthesis of ditrifluoroacetate.
Yield 1.78 g (2.72 mmol) Yield 57.2%
MS (ESI, m / z) 426 (MH +)
H-NMR (DMSO-d6) δ 1.15 (3H, t), 1.88-1.98 (1H, m), 2.01-2.11 (1H, m), 2.45 (2H, ddd), 4.03 (2H, q), 4.11 (1H, dd), 4.19 (1H, dd), 4.38 (1H, br), 7.34 (1H, d), 7.39 (1H, d), 7.40 (1H, s), 7.54 (1H, dd), 7.91 ( 2H, d), 8.05 (2H, d), 8.66 (1H, d), 9.17 (2H, s), 9.29 (4H, s), 9.42 (2H, s)
Example 121
(4R) -4- (4-Amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoic acid Synthesis of ditrifluoroacetate
(4R) -4- (4-Amidinobenzoylamino) -5- (3-amidinophenoxy) ethyl pentanoate 1.02 g (1.56 mmol) of ditrifluoroacetate was used as a starting material, and (3R) -3- ( 4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid The title compound was obtained in the same manner as in the synthesis of ditrifluoroacetate.
Yield 261 mg (0.417 mmol) Yield 26.7%
MS (ESI, m / z) 398 (MH +)
H-NMR (DMSO-d6) δ 1.84-1.96 (1H, m), 1.98-2.10 (1H, m), 2.37 (2H, ddd), 4.11 (1H, dd), 4.20 (1H, dd), 4.38 (1H, br), 7.33 (1H, d), 7.39 (1H, d), 7.40 (1H, s), 7.91 (2H, d), 8.05 (2H, d), 8.65 (1H, d), 9.18 ( 2H, s), 9.26 (2H, s), 9.29 (2H, s), 9.41 (2H, s)
Example 122
N- [3- (3-Amidinophenoxy) propyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Synthesis of 4- [3- (3-amidinophenoxy) propylcarbamoylbenzoic acid ethyl trifluoroacetate
Process 1
Synthesis of N- (3-bromopropyl) -t-butylcarbamate
By using the same procedure as in Step 1 of Example 1, starting from 18.4 g (84.2 mmol) of 3-bromopropylamine hydrobromide and 13.1 g (60.0 mmol) of di-t-butyl dicarbonate. The title compound was obtained.
Yield 11.8 g (50.0 mmol) Yield 83%
H-NMR (CDCl3) δ1.42 (9H, s), 2.05 (2H, tt), 3.25 (2H, dt), 3.45 (2H, t) 4.70 (1H, br)
Process 2
Synthesis of 3- [3- (t-butoxycarbonylamino) propoxy] benzonitrile
Starting from 6 g (25.2 mmol) of N- (3-bromopropyl) -t-butylcarbamate and 2 g (16.8 mmol) of 3-hydroxybenzonitrile, the title compound was prepared in the same manner as in Step 2 of Example 1. Got.
Yield 4.51 g (16.3 mmol) Yield 96%
H-NMR (CDCl3) δ1.42 (9H, s), 2.00 (2H, tt), 3.35 (2H, dt), 4.05 (2H, t), 4.70 (1H, br), 7.12 (1H, d), 7.14 (1H, s), 7.24 (1H, d), 7.37 (1H, t)
Process 3
Synthesis of 3- (3-aminopropoxy) benzonitrile hydrochloride
The title compound was obtained in the same manner as in Step 3 of Example 1, using 1 g (3.6 mmol) of 3- [3- (t-butoxycarbonylamino) propoxy] benzonitrile as a starting material.
Yield 758 mg (3.6 mmol) Yield 100%
Process 4
Synthesis of N- [3- (3-cyanophenoxy) propyl] -4-cyanobenzamide
Starting from 100 mg (0.47 mmol) of 3- (3-aminopropoxy) benzonitrile hydrochloride and 77 mg (0.52 mmol) of 4-cyanobenzoic acid, the title compound was obtained in the same manner as in Step 4 of Example 1. It was.
Yield 124 mg (0.41 mmol) Yield 87%
H-NMR (CDCl3) δ 2.18 (2H, tt), 3.70 (2H, dt), 4.15 (2H, t), 6.50 (1H, br), 7.15 (1H, d), 7.18 (1H, s), 7.25 (1H, d), 7.38 (1H, t), 7.75 (2H, d), 7.85 (2H, d)
Process 5
N- [3- (3-Amidinophenoxy) propyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Synthesis of ethyl 4- [3- (3-amidinophenoxy) propylcarbamoyl] benzoate trifluoroacetate
The title compound was obtained by the same procedures as in Step 5 of Example 95, using 125 mg (0.41 mmol) of N- [3- (3-cyanophenoxy) propyl] -4-cyanobenzamide as a starting material.
N- [3- (3-Amidinophenoxy) propyl] -4-amidinobenzamide ditrifluoroacetate:
Yield 3 mg (0.01 mmol) Yield 2%
MS (ESI, m / z) 340 (MH +)
H-NMR (DMSO-d6) δ2.05 (2H, tt), 3.50 (2H, dt), 4.18 (2H, t), 7.31 (1H, d), 7.38 (1H, s), 7.39 (1H, d ), 7.54 (1H, s), 7.89 (2H, d), 8.04 (2H, d), 8.80 (1H, br), 9.10 (2H, br), 9.20 (2H, br), 9.30 (2H, br) , 9.40 (2H, br)
4- [3- (3-Amidinophenoxy) propylcarbamoyl ethyl benzoate trifluoroacetate:
MS (ESI, m / z) 370 (MH +)
H-NMR (DMSO-d6) δ1.35 (3H, t), 2.05 (2H, tt), 3.45 (2H, dt), 4.15 (2H, t), 4.35 (2H, q), 7.32 (1H, d ), 7.38 (1H, d), 7.37 (2H, s), 7.55 (1H, t), 7.97 (2H, d), 8.04 (2H, d), 8.75 (1H, br), 9.05 (2H, br) , 9.27 (2H, br)
Example 123
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(1-acetyl-4-piperidine) carboxamide trifluoroacetate
Process 1
Synthesis of N- [3- (3-cyanophenoxy) propyl]-(1-acetyl-4-piperidine) carboxamide
Starting from 89 mg (0.52 mmol) of (1-acetyl-4-piperidine) carboxylic acid and 100 mg (0.47 mmol) of 3- (3-aminopropoxy) benzonitrile hydrochloride, the same as in Step 4 of Example 1 The title compound was obtained by manipulation.
Yield 98 mg (0.30 mmol) Yield 64%
H-NMR (CDCl3) δ 1.50-1.90 (4H, m), 2.05 (2H, tt), 2.30 (1H, m), 2.65 (1H, m), 3.10 (1H, m), 3.45 (2H, dt ), 3.85 (1H, m), 4.05 (2H, t), 4.60 (1H, m), 5.75 (1H, br), 7.15 (1H, d), 7.15 (1H, s), 7.25 (1H, d) , 7.40 (1H, t)
Process 2
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(1-acetyl-4-piperidinecarboxamide trifluoroacetate
Using 98 mg (0.30 mmol) of N- [3- (3-cyanophenoxy) propyl]-(1-acetyl-4-piperidinecarboxamide) as a starting material, the title compound was obtained in the same manner as in Step 5 of Example 95. It was.
Yield 72 mg (0.16 mmol) Yield 53%
MS (ESI, m / z) 347 (MH +)
H-NMR (DMSO-d6) δ 1.30-1.50 (2H, m), 1.70 (2H, m), 1.85 (2H, tt), 2.35 (1H, m), 2.55 (1H, m), 3.00 (1H , m), 3.20 (2H, dt), 3.80 (1H, m), 4.05 (2H, t), 4.35 (1H, m), 7.28 (1H, d), 7.35 (1H, s), 7.37 (1H, s), 7.55 (1H, t), 7.90 (1H, br), 9.20 (2H, br), 9.30 (2H, br)
Example 124
N- [3- (3-Amidinophenoxy) propyl] -4-piperidinecarboxamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 3-hydroxybenzamidine hydrochloride
5-Hydroxybenzonitrile (5 g, 42 mmol) was dissolved in 50 ml of ethanol (W / V) containing 30% hydrogen chloride and stirred overnight at room temperature. The residue obtained by distilling off the solvent was dissolved in 50 ml of an ethanol solution containing 30% ammonia (W / V) and stirred overnight at room temperature, and then the solvent was distilled off to obtain the title compound.
Yield 4.4 g (25.5 mmol) Yield 61%
Process 2
Synthesis of Nt-butoxycarbonyl-3-hydroxybenzamidine
3-hydroxybenzamidine hydrochloride 1 g (5.8 mmol), di-t-butyl dicarbonate 1.27 g (5.8 mmol), 4- (dimethylamino) pyridine 24 mg (0.2 mmol), triethylamine 1.30 g (12 .8 mmol) was dissolved in 20 ml of dimethylformamide and stirred overnight at room temperature. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent. Yield 458 mg (1.94 mmol) Yield 33%
H-NMR (DMSO-d6) δ1.45 (9H, s), 6.95 (1H, d), 7.25 (1H, t), 7.35 (1H, d), 7.38 (1H, s), 8.90 (2H, br ), 9.65 (1H, br)
Process 3
Synthesis of Nt-butoxycarbonyl-3- [3- (t-butoxycarbonylamino) propoxy] benzamidine
The title compound was obtained in the same manner as in Step 2 of Example 1 using Nt-butoxycarbonyl-3-hydroxybenzamidine and N- (3-bromopropyl) -t-butylcarbamate as starting materials. H-NMR (CDCl3) δ1.42 (9H, s), 1.55 (9H, s), 3.52 (2H, dt), 4.05 (2H, t), 4.95 (1H, br), 7.03 (1H, d), 7.33 (1H, t), 7.41 (1H, br), 7.47 (1H, br)
Process 4
Synthesis of 3- (3-aminopropoxy) benzamidine dihydrochloride
The title compound was obtained in the same manner as in Step 3 of Example 1 using 3- [3- (t-butoxycarbonylamino) propoxy] -Nt-butoxycarbonylbenzamidine as a starting material.
H-NMR (DMSO-d6) δ 3.20 (2H, br), 4.30 (2H, br), 7.34 (1H, d), 7.49 (1H, d), 7.51 (1H, s), 7.56 (1H, t ), 8.38 (3H, br), 9.29 (2H, br), 9.50 (2H, br)
Process 5
N- [3- (3-Amidinophenoxy) propyl] -4-piperidinecarboxamide Synthesis of ditrifluoroacetate
30 mg (0.13 mmol) of (1-t-butoxycarbonyl-4-piperidine) carboxylic acid and 12 mg (0.12 mmol) of N-methylmorpholine were dissolved in 5 ml of dimethylformamide, and 13 mg (0. 12 mmol), and 5 minutes later, 3-[(3-aminopropyl) oxy] benzamidine 50 mg (0.12 mmol) of ditrifluoroacetate and 24 mg (0.24 mmol) of N-methylmorpholine dissolved in 5 ml of dimethylformamide The mixture was further stirred at room temperature for 4 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. This was dissolved in 10 ml of 4N hydrogen chloride in dioxane and stirred at room temperature for 2 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield: 32 mg (0.06 mmol) Yield 50%
MS (ESI, m / z) 305 (MH +)
H-NMR (DMSO-d6) δ 1.62-1.95 (6H, m), 2.40 (1H, m), 2.90 (2H, m), 3.20-3.38 (4H, m), 4.10 (2H, t), 7.28 (1H, d), 7.38 (1H, s), 7.39 (1H, d), 7.53 (1H, t), 8.04 (1H, br), 8.46 (1H, br), 8.78 (1H, br), 9.30 ( 2H, br), 9.42 (2H, br)
Example 125
N- [3- (3-Amidinophenoxy) propyl] -4-aminobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of ethyl 4- (t-butoxycarbonylamino) benzoate
The title compound was obtained in the same manner as in Step 1 of Example 1, using ethyl 4-aminobenzoate and di-t-butyl dicarbonate as starting materials.
H-NMR (CDCl3) δ1.38 (3H, t), 1.55 (9H, s), 4.35 (2H, q), 6.65 (1H, br), 7.42 (2H, d), 7.95 (2H, d)
Process 2
Synthesis of 4- (t-butoxycarbonylamino) benzoic acid
The title compound was obtained by the same procedures as in Step 2 of Example 97 using ethyl 4- (t-butoxycarbonylamino) benzoate as a starting material.
Process 3
N- [3- (3-Amidinophenoxy) propyl] -4-aminobenzamide Synthesis of ditrifluoroacetate
Starting material: 50 mg (0.126 mmol) of 3- (aminopropoxy) benzamidine ditrifluoroacetate, 30 mg (0.126 mmol) of 4- [t-butoxycarbonylamino] benzoic acid 4- [t-butoxycarbonylamino] benzoic acid In the same manner as in Step 5 of Example 124, the title compound was obtained.
Yield 9.5 mg (0.018 mmol) Yield 15%
MS (ESI, m / z) 313 (MH +)
H-NMR (DMSO-d6) δ 1.95 (2H, tt), 3.35 (2H, dt), 4.10 (2H, t), 6.57 (2H, d), 7.30 (1H, d), 7.36 (1H, s ), 7.37 (1H, d), 7.53 (1H, t) 7.58 (2H, d), 8.08 (1H, br), 9.10 (2H, br), 9.30 (2H, br)
Example 126
Synthesis of N- [3- (3-amidinophenoxy) propyl] -4- (aminomethyl) benzamide ditrifluoroacetate
3- (aminopropoxy) benzamidine ditrifluoroacetate 80 mg (0.19 mmol), 4- (t-butoxycarbonylamino) methylbenzoic acid 48 mg (0.19 mmol) as starting materials, as in Step 5 of Example 124 To give the title compound.
Yield 25 mg (0.045 mmol) Yield 24%
MS (ESI, m / z) 327 (MH +)
H-NMR (DMSO-d6) δ2.00 (2H, tt), 3.40 (2H), 4.02-4.18 (4H, m), 7.29 (1H, d), 7.36-7.40 (2H, m), 7.48-7.54 (3H, m), 7.88 (2H, d), 8.38 (3H, br), 8.60 (1H, br), 9.30 (2H, br), 9.42 (2H, br)
Example 127
Synthesis of N- [3- (3-amidinophenoxy) propyl] -3-amidinobenzamide ditrifluoroacetate
Synthesis of ethyl 3- [3- (3-amidinophenoxy) propylcarbamoyl] benzoate trifluoroacetate
Process 1
Synthesis of N- [3- (3-cyanophenoxy) propyl] -3-cyanobenzamide
The title compound was obtained in the same manner as in Step 4 of Example 1, using 3-cyanobenzoic acid and 3- (3-aminopropoxy) benzonitrile hydrochloride as starting materials.
Process 2
N- [3- (3-Amidinophenoxy) propyl] -3-amidinobenzamide Synthesis of ditrifluoroacetate
Synthesis of ethyl 3- [3- (3-amidinophenoxy) propylcarbamoyl] benzoate trifluoroacetate
The title compound was obtained by the same procedures as in Step 5 of Example 95, using 125 mg (0.41 mmol) of N- [3- (3-cyanophenoxy) propyl] -3-cyanobenzamide as a starting material.
N- [3- (3-Amidinophenoxy) propyl] -3-amidinobenzamide ditrifluoroacetate:
Yield 3 mg (0.005 mmol) Yield 1%
MS (ESI, m / z) 340 (MH +)
H-NMR (DMSO-d6) δ2.05 (2H, tt), 3.50 (2H, dt), 4.20 (2H, t), 7.31 (1H, d), 7.38 (1H, s), 7.39 (1H, d ), 7.54 (1H, t), 7.72 (1H, t), 7.94 (1H, d), 8.18 (1H, d) 8.26 (1H, s), 8.75 (1H, br), 9.11 (2H, br), 9.21 (2H, br), 9.27 (2H, br), 9.38 (2H, br)
3- [3- (3-Amidinophenoxy) propylcarbamoyl] ethyl benzoate trifluoroacetate:
MS (ESI, m / z) 370 (MH +)
H-NMR (DMSO-d6) δ1.35 (3H, t), 2.05 (2H, tt), 3.50 (2H, dt), 4.15 (2H, t), 4.35 (2H, q), 7.32 (1H, d ), 7.38 (1H, s), 7.39 (1H, d), 7.54 (1H, t), 7.63 (1H, t), 8.09 (1H, d), 8.13 (1H, d), 8.44 (1H, s) , 8.78 (1H, br), 9.15 (2H, br), 9.28 (2H, br)
Example 128
Synthesis of 3- [3- (2-naphthalenesulfonylamino) propoxy] benzamidine trifluoroacetate
Process 1
Synthesis of 3- [3- (2-naphthalenesulfonylamino) propoxy] benzonitrile
The title compound was obtained in the same manner as in Step 1 of Example 110, using 2-naphthalenesulfonyl chloride and 3- (3-aminopropoxy) benzonitrile as starting materials.
H-NMR (CDCl3) δ 2.00 (2H, tt), 3.25 (2H, dt), 3.95 (2H, t), 4.80 (1H, br), 6.95 (1H, s), 7.00 (1H, d), 7.20 (1H, d), 7.30 (1H, t), 7.55-7.70 (2H, m), 7.80-8.00 (4H, m), 8.42 (1H, s)
Process 2
Synthesis of 3- [3- (2-naphthalenesulfonylamino) propoxy] benzamidine trifluoroacetate
The title compound was obtained by the same procedures as in Step 5 of Example 95, using 300 mg (0.82 mmol) of 3- [3- (2-naphthalenesulfonylamino) propoxy] benzonitrile as a starting material.
Yield 169 mg (0.34 mmol) Yield 41%
MS (FAB, m / z) 384 (MH +)
H-NMR (DMSO-d6) δ1.85 (2H, tt), 3.00 (2H, dt), 4.00 (2H, t), 7.17 (1H, d), 7.25 (1H, s), 7.35 (1H, d ), 7.45 (1H, t), 7.62-8.16 (7H, m), 8.43 (1H, s), 9.18 (2H, br), 9.24 (2H, br)
Example 129
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2R) -2- (benzyloxycarbonylamino) propionamide trifluoroacetate
3- (aminopropoxy) benzamidine dihydrochloride 30 mg (0.11 mmol), N-benzyloxycarbonyl-D-alanine 25.8 mg (0.135 mmol), 1-hydroxybenzotriazole 23.0 mg (0.17 mmol), 1 -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 25.9 mg (0.135 mmol) and N-methylmorpholine 23 mg (0.23 mmol) were dissolved in 2 ml of dimethylformamide and stirred overnight. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequently, the obtained residue was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and containing 0.1% trifluoroacetic acid (v / v) of water and acetonitrile. The title compound was obtained by elution with a mixed solvent and freeze-drying the fraction of interest.
Yield 5 mg (0.01 mmol) Yield 7%
MS (ESI, m / z) 399 (MH +)
H-NMR (DMSO-d6) δ 1.20 (3H, d), 1.90 (2H, tt), 3.25 (2H, dt), 3.92-4.10 (3H, m), 5.00 (2H, m), 7.26-7.44 (8H, m), 7.53 (1H, t), 7.97 (1H, br), 9.10 (2H, br), 9.30 (2H, br)
Example 130
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2S) -2- (benzyloxycarbonylamino) propionamide trifluoroacetate
By using the same procedure as in Step 5 of Example 124, starting from 3- (aminopropoxy) benzamidine dihydrochloride (3.0 mg, 0.11 mmol) and N-benzyloxycarbonyl-L-alanine (26 mg, 0.135 mmol). The title compound was obtained.
Yield 17 mg (0.03 mmol) Yield 22%
MS (ESI, m / z) 399 (MH +)
H-NMR (DMSO-d6) δ 1.20 (3H, d), 1.90 (2H, tt), 3.25 (2H, dt), 3.92-4.10 (3H, m), 5.00 (2H, m), 7.26-7.44 (8H, m), 7.53 (1H, t), 7.97 (1H, br), 9.10 (2H, br), 9.30 (2H, br)
Example 131
Synthesis of (4S) -4- [3- (3-amidinophenoxy) propyl] carbamoyl-4- (benzyloxycarbonylamino) butanoic acid trifluoroacetate
Step 1 of Example 129 using 30 mg (0.11 mmol) of 3- (aminopropoxy) benzamidine dihydrochloride and 46 mg (0.135 mmol) of N-benzyloxycarbonyl-L-glutamic acid-γ-t-butyl ester as starting materials. To give the t-butyl ester of the title compound. Subsequently, this was dissolved in a 4N hydrogen chloride dioxane solution and stirred for 5 hours. The solvent was distilled off, and the resulting residue was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 12 mg (0.02 mmol) Yield 15%
MS (ESI, m / z) 457 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.95 (4H, m), 2.25 (2H, t), 3.23 (2H, dt), 3.85-4.05 (3H, m), 4.95-5.05 (2H, m) , 7.27-7.38 (7H, m), 7.44 (1H, d), 7.52 (1H, t), 8.02 (1H, t), 9.00 (2H, br), 9.30 (2H, br)
Example 132
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2S) -2- (t-butoxycarbonylamino) -3- (4-imidazolyl) propanamide ditrifluoroacetate
Process 1
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2- (t-butoxycarbonylamino) -3- [1- (4-toluenesulfonyl) -4-imidazolyl] propanamide ditrifluoroacetic acid Salt synthesis
Example 124 starting from 3- (aminopropoxy) benzamidine dihydrochloride, (2S) -2- (t-butoxycarbonylamino) -3- [1- (4-toluenesulfonyl) -4-imidazolyl] propionic acid The title compound was obtained in the same manner as in Step 5.
Process 2
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2S) -2- (t-butoxycarbonylamino) -3- (4-imidazolyl) propanamide ditrifluoroacetate
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2- (t-butoxycarbonylamino) -3- [1- (4-toluenesulfonyl) -4-imidazolyl] propanamide ditrifluoroacetic acid 40 mg (0.05 mmol) of salt, 13.5 mg (0.1 mmol) of 1-tohydroxybenztriazole was dissolved in 2 ml of tetrahydrofuran, and the mixture was stirred overnight at room temperature. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 23 mg (0.035 mmol) Yield 70%
MS (ESI, m / z) 431 (MH +)
H-NMR (DMSO-d6) δ 1.35 (9H, s), 1.85 (2H, tt), 2.80-3.10 (2H, m), 3.25 (2H, dt), 4.05 (2H, t), 4.20 (1H , m), 7.11 (1H, d), 7.26-7.40 (4H, m), 7.53 (1H, t), 8.03 (1H, br), 8.95 (1H, s), 9.15 (2H, br), 9.25 ( (2H, br)
Example 133
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2S) -2- (benzyloxycarbonylamino) -3- (4-imidazolyl) propanamide ditrifluoroacetate
Process 1
Synthesis of (2S) -2-amino-3- [1- (4-toluenesulfonyl) -4-imidazolyl] propionic acid ditrifluoroacetate
5 g of (2S) -2- (t-butoxycarbonylamino) -3- [1- (4-toluenesulfonyl) -4-imidazolyl] propionic acid was stirred in trifluoroacetic acid at room temperature for 2 hours. The solvent was distilled off, the residue was suspended in dichloromethane, collected by filtration, and dried in vacuo to give the title compound.
Yield 6.00 g
H-NMR (DMSO-d6) δ2.40 (3H, s), 3.00 (2H, m), 4.18 (1H, brs), 7.48-7.56 (3H, m), 7.96 (2H, d), 8.20 (3H , brs), 8.36 (1H, d)
Process 2
Synthesis of (2S) -2- (benzyloxycarbonylamino) -3- [1- (4-toluenesulfonyl) -4-imidazolyl] propionic acid
(2S) -2-Amino-3- [1- (4-toluenesulfonyl) -4-imidazolyl] propionic acid 1 g (2.4 mmol) of ditrifluoroacetate and 840 mg (10 mmol) of sodium hydrogen carbonate are dissolved in 30 ml of water. Then, 2.4 ml (15 mmol) of benzyl chloroformate was dissolved in 30 ml of ether and added thereto. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the aqueous layer was washed with ether. Subsequently, hydrochloric acid was added to the aqueous layer to make it acidic, and the title compound was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent.
Yield 628mg
H-NMR (DMSO-d6) δ 2.30 (3H, s), 2.90-3.20 (2H, m), 4.35 (1H, brs), 5.00-5.10 (3H, m), 7.12 (2H, d), 7.27 -7.40 (7H, m), 7.49 (2H, d)
Process 3
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2S) -2- (benzyloxycarbonylamino) -3- (4-imidazolyl) propanamide ditrifluoroacetate
Example 2 Starting from (2S) -2- (benzyloxycarbonylamino) -3- [1- (4-toluenesulfonyl) -4-imidazolyl] propionic acid, 3- (aminopropoxy) benzamidine dihydrochloride The title compound was obtained in the same manner as in Step 5.
MS (ESI, m / z) 465 (MH +)
H-NMR (DMSO-d6) δ1.90 (2H, tt), 2.85-3.15 (2H, m), 3.25 (2H, dt), 4.05 (2H, t), 4.30 (1H, m), 4.95-5.05 (2H, m), 7.24-7.40 (9H, m), 7.53 (1H, t), 8.50 (1H, br), 8.96 (1H, s), 9.17 (2H, brs), 9.28 (2H, brs)
Example 134
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2S, 3S) -2- (benzyloxycarbonylamino) -3-methylpentanamide trifluoroacetate
The title compound was prepared in the same manner as in Step 5 of Example 124, using 70 mg (0.28 mmol) of 3- (aminopropoxy) benzamidine dihydrochloride and 70 mg (0.26 mmol) of N-benzyloxycarbonyl-L-isoleucine as starting materials. Got.
Yield 33 mg (0.06 mmol) Yield 23%
MS (ESI, m / z) 441 (MH +)
H-NMR (DMSO-d6) δ 0.78-0.83 (6H, m), 1.10 (1H, m), 1.40 (1H, m), 1.70 (1H, m), 1.90 (2H, m), 3.22 (2H , m), 3.80 (1H, t), 4.05 (2H, t), 5.00 (2H, m), 7.22-7.40 (8H, m), 7.55 (1H, t), 8.05 (1H, br), 9.03 ( 2H, br), 9.30 (2H, br)
Example 135
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2- (benzyloxycarbonylamino) -6-aminohexanamide Synthesis of ditrifluoroacetate
The starting materials were 70 mg (0.28 mmol) of 3- (aminopropoxy) benzamidine dihydrochloride and 99 mg (0.26 mmol) of N-α-benzyloxycarbonyl-N-ε-t-butoxycarbonyl-L-lysine. The title compound, t-butyl carbamate, was obtained by an operation similar to 124, Step 5. Subsequently, this was dissolved in a 4N hydrogen chloride dioxane solution and stirred for 5 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilizing the fraction of interest. Yield 70 mg (0.1 mmol) Yield 38%
MS (ESI, m / z) 456 (MH +)
H-NMR (DMSO-d6) δ 1.30 (2H, m), 1.43-1.61 (4H, m), 1.90 (2H, m), 2.75 (2H, m), 3.23 (2H, m), 3.90 (1H , m), 4.05 (2H, t), 5.01 (2H), 7.26-7.41 (8H, m), 7.53 (1H, t), 7.69 (3H, br), 8.23 (1H, br), 9.15 (2H, br), 9.30 (2H, br)
Example 136
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2S) -2- (benzyloxycarbonylamino) -3-phenylpropanamide trifluoroacetate
The title compound was prepared in the same manner as in Step 5 of Example 124, using 30 mg (0.11 mmol) of 3- (aminopropoxy) benzamidine dihydrochloride and 40 mg (0.135 mmol) of N-benzyloxycarbonyl-L-phenylalanine as starting materials. Got.
Yield 7 mg (0.012 mmol) Yield 9%
MS (ESI, m / z) 475 (MH +)
H-NMR (DMSO-d6) δ1.82 (2H), 2.70-3.00 (2H, m), 3.23 (2H, m), 4.00 (2H, t), 4.20 (1H, m), 4.90-5.00 (4H , m), 7.17-7.40 (12H, m), 7.50-7.60 (2H), 8.10 (1H, br), 9.10 (2H, br), 9.30 (2H, br)
Example 137
N- [3- (3-Amidinophenoxy) propyl]-(2R) -2- (benzyloxycarbonylamino) -3-phenylpropanamide trifluoroacetate
The title compound was prepared in the same manner as in Step 5 of Example 124, using 70 mg (0.28 mmol) of 3- (aminopropoxy) benzamidine dihydrochloride and 78 mg (0.26 mmol) of N-benzyloxycarbonyl-D-phenylalanine as starting materials. Got.
Yield 14.1 mg (0.024 mmol) Yield 9%
MS (ESI, m / z) 475 (MH +)
H-NMR (DMSO-d6) δ1.82 (2H), 2.70-3.00 (2H, m), 3.23 (2H, m), 4.00 (2H, t), 4.20 (1H, m), 4.90-5.00 (4H , m), 7.17-7.40 (12H, m), 7.50-7.60 (2H), 8.10 (1H, br), 9.05 (2H, br), 9.30 (2H, br)
Example 138
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2-aminopropanamide Synthesis of ditrifluoroacetate
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2- (benzyloxycarbonylamino) propanamide trifluoroacetate 11 mg (0.02 mlol) was dissolved in 1 ml of ethanol and 1 mg of 10% palladium carbon was obtained. And stirred at room temperature for 5 hours under a hydrogen atmosphere of 1 atm. Palladium on carbon was removed by suction filtration, and water containing 0.1% trifluoroacetic acid (v / v) was added to the filtrate, followed by concentration to give the title compound.
Yield 7 mg (0.014 mmol) Yield 70%
MS (ESI, m / z) 349 (MH + + DMSO-d6)
H-NMR (DMSO-d6) δ 1.35 (3H, d), 1.90 (2H, tt), 3.30 (2H, dt), 3.80 (1H, br), 4.10 (2H, t), 7.30 (1H, d ), 7.37 (1H, s), 7.39 (1H, d), 7.54 (1H, t), 8.12 (3H, br), 8.52 (1H, br), 9.31 (2H, br), 9.37 (2H, br)
Example 139
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2-amino-3- (4-imidazolyl) propanamide Synthesis of tritrifluoroacetate
10 mg of N- [3- (3-amidinophenoxy) propyl]-(2S) -2- (t-butoxycarbonylamino) -3- (4-imidazolyl) propanamide ditrifluoroacetate was added to 4N hydrogen chloride dioxane. Dissolved in the solution and stirred for 2 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 7 mg (0.010 mmol) Yield 67%
MS (ESI, m / z) 331 (MH +)
H-NMR (DMSO-d6) δ 1.85 (2H, m), 3.15 (2H, m), 3.30 (2H, dt), 4.02-4.12 (3H, m), 7.28 (1H, d), 7.34-7.42 (3H, m), 7.54 (1H, t), 8.40 (3H, br), 8.60 (1H, br), 8.85 (1H, s), 9.30 (4H, br)
Example 140
N- [3- (3-Amidinophenoxy) propyl]-(2S, 3S) -2-amino-3-methylpentanamide Synthesis of ditrifluoroacetate
Conducted using 28 mg (0.050 mmol) of N- [3- (3-amidinophenoxy) propyl]-(2S, 3S) -2- (benzyloxycarbonylamino) -3-methylpentanamide trifluoroacetate as a starting material The title compound was obtained in the same manner as the Example 138.
Yield 25 mg (0.047 mmol) Yield 94%
MS (ESI, m / z) 307 (MH +)
H-NMR (DMSO-d6) δ0.80-0.90 (6H, m), 1.05 (1H, m), 1.43 (1H, m), 1.80 (1H, m), 1.95 (2H, m), 3.20-3.40 (2H, m), 3.55 (1H, br), 4.10 (2H, t), 7.29 (2H, d), 7.37 (1H, s), 7.39 (1H, d), 7.55 (1H, t), 8.13 ( 3H, br), 8.55 (1H, br), 9.28 (2H, br), 9.32 (2H, br)
Example 141
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2,6-diaminohexanamide Synthesis of tritrifluoroacetate
N- [3- (3-Amidinophenoxy) propyl]-(2S) -2- (benzyloxycarbonylamino) -6-aminohexanamide 20 mg (0.03 mmol) of ditrifluoroacetate as a starting material, Examples The title compound was obtained in the same manner as in 138.
Yield 17 mg (0.026 mmol) Yield 87%
MS (ESI, m / z) 322 (MH +)
H-NMR (DMSO-d6) δ1.35 (2H, m), 1.55 (2H, m), 1.70 (2H, m), 1.90 (2H, tt), 2.75 (2H, br), 3.30 (2H, dt ), 3.60-3.90 (1H), 4.10 (2H, t), 7.28 (2H, d). 7.38 (2H, s), 7.40 (2H, d), 7.54 (1H, t), 7.90 (3H, br) , 8.24 (3H, br), 8.66 (1H, br), 9.34 (2H, br), 9.53 (2H, br)
Example 142
Synthesis of N- [3- (3-amidinophenoxy) propyl]-(2R) -2-amino-3-phenylpropanamide ditrifluoroacetate
N- [3- (3-Amidinophenoxy) propyl]-(2R) -2- (benzyloxycarbonylamino) -3-phenylpropanamide 10 mg (0.017 mmol) of ditrifluoroacetate as a starting material, Examples The title compound was obtained in the same manner as in 138.
Yield 8 mg (0.014 mmol) Yield 82%
MS (ESI, m / z) 349 (MH +)
H-NMR (DMSO-d6) δ1.75 (2H, m), 3.00 (2H, d), 3.05-3.35 (2H, m), 3.85-4.00 (3H, m), 7.20-7.34 (7H, m) , 7.40 (1H, d), 7.54 (1H, t), 8.28 (3H, br), 8.50 (1H, br), 9.31 (2H, br), 9.38 (2H, br)
Example 143
Synthesis of N- [2- (3-amidinophenylthio) ethyl] -4-amidinobenzamide ditrifluoroacetate
Process 1
Synthesis of benzyl-N- (2-bromoethyl) carbamate
10 g (49 mmol) of 2-bromoethylamine bromate and 15 ml of triethylamine were dissolved in dichloromethane, and 7.8 ml (49 mmol) of benzyl chloroformate was added under ice cooling, followed by stirring at room temperature. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 10.6 g (41 mmol) Yield 84%
H-NMR (CDCl3) δ3.45 (2H, t), 3.60 (2H, dt), 5.10 (2H, s), 5.20 (1H, brs), 7.30-7.38 (5H, m)
Process 2
Synthesis of 3-mercaptobenzonitrile
2 g (17 mmol) of 3-aminobenzonitrile was suspended in 6N hydrogen chloride, and 1.17 g (17 mmol) of sodium nitrite was dissolved in cold water and added while keeping the temperature at 4 ° C. or lower. The reaction solution was poured into an aqueous solution of 3.04 g (19 mmol) of potassium O-ethyldithiocarbonate heated to 45 ° C., and the mixture was further stirred at 45 ° C. for 2 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequently, purification was performed by silica gel column chromatography to obtain dithiocarbonate-O-ethyl-S- (3-cyanophenyl).
Subsequently, this was dissolved in ethanol under an argon atmosphere and heated to reflux, 500 mg of potassium hydroxide was added, and the mixture was refluxed again for 4 hours. The residue obtained by distilling off the solvent was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain the title compound.
Yield 446 mg (3.30 mmol) Yield 19%
H-NMR (CDCl3) δ3.60 (1H, s), 7.33 (1H, t), 7.44 (1H, d), 7.49 (1H, d), 7.54 (1H, s)
Process 3
Synthesis of 3- [2- (benzyloxycarbonylamino) ethylthio] benzonitrile
440 mg (3.3 mmol) of 3-mercaptobenzonitrile, 460 mg (3.3 mmol) of potassium carbonate, 1.0 g (4 mmol) of N-benzyl- (2-bromoethyl) carbamate, 160 mg (0.5 mmol) of tetrabutylammonium bromide It was dissolved in formamide and stirred at room temperature for 4 hours under an argon atmosphere. The residue obtained by distilling off the solvent was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 414 mg (1.3 mmol) Yield 39%
H-NMR (CDCl3) δ 3.10 (2H, t), 3.40 (2H, dt), 5.10 (3H, brs), 7.31-7.40 (6H, m), 7.45 (1H, d), 7.57 (1H, brd ), 7.59 (1H, brs)
Process 4
Synthesis of (2-aminoethylthio) benzonitrile hydrochloride
400 mg (1.26 mmol) of 3- [2- (benzyloxycarbonylamino) ethylthio] benzonitrile was dissolved in acetic acid containing 20% hydrogen bromide and stirred at room temperature for 2 hours. The residue obtained by distilling off the solvent was dissolved in 1N hydrogen chloride, washed with ethyl acetate, made alkaline with 1N aqueous sodium hydroxide solution, and treated with ethyl acetate as an extraction solvent in the usual manner. Got. Yield 190 mg (1.1 mmol) Yield 84%
H-NMR (CDCl3) δ2.95 (2H, t), 3.05 (2H, t), 7.38 (1H, t), 7.45 (1H, d), 7.55 (1H, d), 7.59 (1H, s)
Process 5
Synthesis of N- [2- (3-cyanophenylthio) ethyl] -4-cyanobenzamide
The title compound was obtained in the same manner as in Step 4 of Example 1, using (2-aminoethylthio) benzonitrile hydrochloride 190 mg (1.1 mmol) and 4-cyanobenzoic acid 177 mg (1.2 mmol) as starting materials. .
Yield 223 mg (0.73 mmol) Yield 66%
H-NMR (CDCl3) δ3.25 (2H, t), 3.70 (2H, dt), 6.50 (1H, brt), 7.40 (1H, t), 7.43 (1H, d), 7.61 (1H, d), 7.64 (1H, s), 7.75 (2H, d), 7.83 (2H, d)
Step 6
Synthesis of N- [2- (3-amidinophenylthio) ethyl] -4-amidinobenzamide
The title compound was obtained in the same manner as step 5 of example 95, using 210 mg (0.68 mmol) of N- [2- (3-cyanophenylthio) ethyl] -4-cyanobenzamide as a starting material. Yield 137 mg (0.24 mmol) Yield 35%
MS (ESI, m / z) 342 (MH +)
H-NMR (DMSO-d6) δ3.30 (2H, t), 3.55 (2H, m), 7.57 (1H, t), 7.60 (1H, d), 7.75 (1H, d), 7.80 (1H, s ), 7.91 (2H, d), 8.02 (2H, d), 9.03 (1H, brt), 9.26 (2H, brs), 9.31 (4H, brs), 9.41 (2H, brs)
Example 144
N- [3- (3-Amidinophenyl) propyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 3- (3-bromopropyl) benzonitrile
1.5 g (8.56 mmol) of 3- (3-cyanophenyl) propionic acid and 1.19 ml (8.56 mmol) of triethylamine were dissolved in 42 ml of tetrahydrofuran, and 0.819 ml (8.56 mmol) of ethyl chloroformate was dissolved under ice cooling. Added and stirred for 20 minutes. The resulting precipitate was removed by suction filtration, and 3 g of ice and 0.648 g (17.12 mmol) of sodium borohydride were added to the filtrate under ice cooling and stirred for 1 hour. 20 ml of 1N aqueous hydrogen chloride solution was added thereto, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. The oily residue thus obtained was dissolved in 86 ml of dichloromethane, and 5.68 g (17.12 mmol) of carbon tetrabromide and 2.69 g (10.27 mmol) of triphenylphosphine were added and stirred at room temperature for 1 hour. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.48 g (6.59 mmol) Yield 77%
Process 2
Synthesis of N- [3- (3-cyanophenyl) propyl] -4-cyanobenzamide
Under an argon atmosphere, 267 mg (7.23 mmol) of sodium hydride (65%) was dissolved in 8 ml of DMF, 1.43 g (6.57 mmol) of di-t-butyliminodicarboxylate was added, and the mixture was stirred at room temperature for 30 minutes. To this, 1.47 g (6.57 mmol) of 3- (3-bromopropyl) benzonitrile was added and stirred at 45 ° C. for 3 hours. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. The oily residue thus obtained was dissolved in 4N hydrogen chloride in dioxane and stirred at room temperature for 4 hours. The oily residue obtained by distilling off the solvent was dissolved in 10 ml of dichloromethane, 1.63 g (9.86 mmol) of 4-cyanobenzoyl chloride and 1.83 ml (13.4 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 5 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.35 g (4.66 mmol) Yield 71%
H-NMR (CDCl3) δ1.98 (2H, quint), 2.76 (2H, t), 3.50 (2H, dt), 6.94 (1H, br), 7.36-7.50 (4H, m), 7.69 (2H, d ), 7.89 (2H, d)
Process 3
N- [3- (3-Amidinophenyl) propyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
800 mg (2.76 mmol) of N- [3- (3-cyanophenyl) propyl] -4-cyanobenzamide was added to 8 ml of (W / V) ethanol containing 30% hydrogen chloride and stirred overnight at room temperature. Subsequently, the mixture was dissolved in 30 ml of an ethanol solution containing 10% ammonia (w / v) at room temperature and stirred overnight at room temperature. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 130 mg (0.236 mmol) Yield 8.5%
MS (ESI, m / z) 324 (MH +)
H-NMR (DMSO-d6) δ1.91 (2H, quint), 2.75 (2H, t), 3.34 (2H, dt), 7.50-7.70 (4H, m), 7.89 (2H, d), 8.03 (2H , d), 8.79 (1H, t), 9.14 (2H, s), 9.27 (4H, s), 9.40 (2H, s)
Example 145
N-[(2E) -3- (3-amidinophenyl) -2-propenyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of 3-[(1E) -3-bromo-1-propenyl] benzonitrile
Starting from 2.5 g (14.4 mmol) of (3E) -3- (3-cyanophenyl) acrylic acid as a starting material, the title compound was obtained in the same manner as the synthesis of 3- (3-bromopropyl) benzonitrile. Yield 3.04 g (13.68 mmol) Yield 95%
Process 2
Synthesis of N-[(2E) -3- (3-cyanophenyl) -2-propenyl] -4-cyanobenzamide
Synthesis of N- [3- (3-cyanophenyl) propyl] -4-cyanobenzamide using 3.65 g (16.44 mmol) of 3-[(1E) -3-bromo-1-propenyl] benzonitrile as a starting material The title compound was obtained in the same manner as in.
Yield 3.02 g (10.52 mmol) Yield 64%
H-NMR (CDCl3) δ 4.27 (1H, dd), 6.35 (1H, dt), 6.56 (1H, d), 7.16 (1H, br), 7.37-7.59 (4H, m), 7.72 (2H, d ), 7.96 (2H, d)
Process 3
N-[(2E) -3- (3-amidinophenyl) -2-propenyl] 4-amidinobenzamide Synthesis of ditrifluoroacetate
N-[(2E) -3- (3-cyanophenyl) -2-propenyl] -4-cyanobenzamide 780 mg (2.71 mmol) as a starting material N- [3- (3-amidinophenyl) propyl] -4 -The title compound was obtained according to the same procedure as the synthesis of amidinobenzamide.
Yield 33 mg (0.06 mmol) Yield 2.2%
MS (ESI, m / z) 322 (MH +)
H-NMR (DMSO-d6) δ4.15 (2H, t), 6.55 (1H, dt), 6.65 (1H, d), 7.58 (1H, dd), 7.68 (1H, d), 7.79 (1H, d ), 7.89 (1H, s), 7.92 (2H, d), 8.10 (2H, d), 9.10 (1H, t), 9.21 (2H, s), 9.32 (4H, s), 9.41 (2H, s)
Example 146
Synthesis of N- [2- (5-amidino-2-iodophenoxy) ethyl] -4-amidinobenzamide ditrifluoroacetate
Process 1
Synthesis of 3-hydroxy-4-iodobenzoic acid
30.0 g (217 mmol) of 3-hydroxybenzoic acid was dissolved in 200 ml of acetic acid, and 53.0 g (326 mmol) of iodine monochloride was added at room temperature. After stirring at 45 ° C. for 15 hours, the residue obtained by distilling off the solvent under reduced pressure was washed twice with 500 ml of 1% aqueous sodium thiosulfate solution and twice with 500 ml of water, and dried at 80 ° C. under reduced pressure to give the title compound. Got.
Yield 17.2 g (65.2 mmol) Yield 30%
MS (FAB, m / z) 265 (MH +)
H-NMR (DMSO-d6) δ7.13 (1H, dd), 7.43 (1H, d), 7.80 (1H, d)
Process 2
Synthesis of 3-hydroxy-4-iodobenzonitrile
To a solution of 22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid in 300 ml of tetrahydrofuran, 19.7 ml (206 mmol) of ethyl chloroformate and 28.7 ml (206 mmol) of triethylamine were added at 0 ° C. After stirring for 15 minutes, the produced triethylamine hydrochloride was filtered off, and the filtrate was added at 0 ° C. to 300 ml of a tetrahydrofuran solution obtained by bubbling ammonia. After stirring at room temperature for 10 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 450 ml of dioxane, and 17.4 ml (117 mmol) of trifluoromethanesulfonic anhydride and 21.8 ml (269 mmol) of pyridine were added at 0 ° C. . After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the resulting residue was treated according to a conventional method using chloroform as an extraction solvent to obtain an oily residue. To a solution of the obtained residue in 180 ml of tetrahydrofuran: methanol (1: 1), 1N aqueous sodium hydroxide solution (90 ml, 90.0 mmol) was added at room temperature. After stirring for 4 hours, the solvent was distilled off under reduced pressure, and the resulting residue was washed with dichloromethane. Subsequently, the mixture was acidified with 1N hydrogen chloride and treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 9.29 g (37.9 mmol) Yield 42%
MS (FAB, m / z) 246 (MH +)
H-NMR (CDCl3) δ5.63 (1H, br), 6.96 (1H, dd), 7.23 (1H, d), 7.79 (1H, d)
Process 3
Synthesis of 3- (2-aminoethoxy) -4-iodobenzonitrile
Starting from 7.44 g (30.4 mmol) of 3-hydroxy-4-iodobenzonitrile and 6.52 g (36.4 mmol) of Nt-butyl-2-chloroethylcarbamate, starting step 2 in Example 1 and The title compound was obtained in the same manner as in step 3.
Yield 4.90 g (17.0 mmol) Yield 56%
MS (ESI, m / z) 289 (MH +)
H-NMR (DMSO-d6) δ2.90 (2H, t), 4.06 (2H, t), 7.18 (1H, dd), 7.45 (1H, d), 7.99 (1H, d)
Process 4
Synthesis of N- [2- (5-cyano-2-iodophenoxy) ethyl] -4-cyanobenzamide 800 mg (2.47 mmol) of 3- (2-aminoethoxy) -4-iodobenzonitrile, 4-cyanobenzoic acid The title compound was obtained in the same manner as in Step 4 of Example 1 using 436 mg (2.96 mmol) as a starting material.
Yield 940 mg (2.25 mmol) Yield 91%
MS (ESI, m / z) 418 (MH +)
H-NMR (CDCl3) δ2.90 (2H, t), 4.06 (2H, t), 7.18 (1H, dd), 7.45 (1H, d), 7.99 (1H, d)
Process 5
Synthesis of N- [2- (5-amidino-2-iodophenoxy) ethyl] -4-amidinobenzamide ditrifluoroacetate
The title compound was obtained in the same manner as in Step 5 of Example 95, using 200 mg (0.48 mmol) of N- [2- (5-cyano-2-iodophenoxy) ethyl] -4-cyanobenzamide as a starting material.
Yield 93 mg (0.14 mmol) Yield 29%
MS (ESI, m / z) 452 (MH +)
H-NMR (DMSO-d6) δ3.74 (2H, dt), 4.33 (2H, t), 7.18 (1H, d), 7.41 (1H, s), 7.90 (2H, d), 8.03 (1H, d ), 8.06 (2H, d), 8.96 (1H, t), 9.10 (2H, br), 9.16 (2H, br), 9.33 (2H, br), 9.40 (2H, br),
Example 147
3- [4-Amidino-2- [2- (4-amidinophenylcarbamoyl) ethoxy] phenyl] -2-oxopropionic acid Synthesis of ditrifluoroacetate
N- [2- (5-amidino-2-iodophenoxy) ethyl] -4-amidinobenzamide 50 mg (0.074 mmol) of ditrifluoroacetate was dissolved in 0.5 ml of DMF, and 35 mg of di-tert-butyl dicarbonate ( 0.16 mmol) and 0.05 ml (0.37 mmol) of triethylamine were added at 0 ° C. and stirred for 4 hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequently, the resultant was purified by silica gel column chromatography. The obtained compound was dissolved in 0.8 ml of acetonitrile, and 27 mg (0.19 mmol) of methyl-2-acetamide acrylate, 2 mg (0.0095 mmol) of palladium acetate, Tris ( 5.8 mg (0.0019 mmol) of 2-methylphenyl) phosphine and 0.06 ml (0.22 mmol) of tributylamine were added at room temperature. The mixture was stirred at 90 ° C. for 21 hours under an argon atmosphere, and suction filtered, and the filtrate was distilled off under reduced pressure. To the obtained residue, 5 ml of 3N hydrogen chloride was added at room temperature, and the mixture was stirred at 60 ° C. for 30 minutes and further at 110 ° C. for 30 minutes. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilizing the fraction of interest. Yield 4.6 mg (0.0072 mmol) Yield 9.7%
MS (FAB, m / z) 412 (MH +)
H-NMR (DMSO-d6) δ 3.72 (2H, dt), 4.15 (2H, s, keto form), 4.31 (2H, t), 6.81 (1H, s, enol form), 7.36-7.48 (2H, m), 7.88 (2H, d), 8.04 (2H, d), 8.33 (1H, d), 9.02 (1H, t), 9.07 (2H, m), 9.25 (4H, br), 9.40 (2H, br )
Example 148
Synthesis of N- [2- (5-amidino-2-methylphenoxy) ethyl] -4-amidinobenzamide ditrifluoroacetate
Process 1
Synthesis of 3-hydroxy-4-methylbenzonitrile
29.8 g (196 mmol) of 3-hydroxy-4-methylbenzoic acid was dissolved in 450 ml of tetrahydrofuran, and 43.1 ml (450 mmol) of ethyl chloroformate and 62.7 ml (450 mmol) of triethylamine were added at 0 ° C. After stirring for 20 minutes, the produced triethylamine hydrochloride was filtered off, and the filtrate was added to 300 ml of a tetrahydrofuran solution obtained by bubbling ammonia at 0 ° C. After stirring at room temperature for 2 hours, the residue obtained by distilling off the solvent under reduced pressure was dissolved in 500 ml of dioxane, and 38.8 ml (274 mmol) of trifluoromethanesulfonic anhydride and 75 ml (931 mmol) of pyridine were added at 0 ° C. After stirring at room temperature for 18 hours, the residue obtained by distilling off the solvent under reduced pressure was used as an extraction solvent, and an oily residue was obtained by the same isolation operation as in Step 1 of Example 1. To a solution obtained by dissolving the obtained residue in 330 ml of tetrahydrofuran: methanol (1: 1), 165 ml (167 mmol) of 1N aqueous sodium hydroxide solution was added at room temperature. After stirring for 4 hours, the solvent was distilled off under reduced pressure, and the resulting residue was washed with dichloromethane. Subsequently, the reaction mixture was acidified with 1N hydrogen chloride, ethyl acetate was used as an extraction solvent, and a crude product was obtained by the same isolation operation as in Step 1 of Example 1. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 20.1 g (151 mmol) Yield 77%
MS (FAB, m / z) 134 (MH +)
H-NMR (CDCl3) δ2.30 (3H, s), 5.93 (1H, s), 7.08 (1H, s), 7.14 (1H, d), 7.21 (1H, d)
Process 2
Synthesis of 3- (2-aminoethoxy) -4-methylbenzonitrile
13.7 g (103 mmol) of 3-hydroxy-4-methylbenzonitrile,
Using 22.2 g (124 mmol) of Nt-butyl-2-chloroethyl carbamate as a starting material, the title compound was obtained in the same manner as in Step 2 and Step 3 of Example 1.
Yield 6.13 g (34.8 mmol) Yield 34%
MS (ESI, m / z) 261 (M + DMSO + H +)
H-NMR (CDCl3) δ 2.29 (3H, s), 3.14 (2H, t), 4.01 (2H, t), 7.03 (1H, d), 7.17 (1H, dd), 7.22 (1H, d)
Process 3
Synthesis of N- [2- (5-cyano-2-methylphenoxy) ethyl] -4-cyanobenzamide 3- (2-aminoethoxy) -4-methylbenzonitrile 6.13 g (34.8 mmol), 4-cyano Starting from 6.14 g (41.8 mmol) of benzoic acid and 3.7 ml (38.3 mmol) of ethyl chloroformate, the title compound was obtained in the same manner as in Step 4 of Example 1.
Yield 13.9 g (45.6 mmol) Yield> 100%
MS (FAB, m / z) 306 (MH +)
H-NMR (CDCl3) δ 2.28 (3H, s), 3.95 (2H, dd), 4.19 (2H, t), 7.05 (1H, s), 7.22 (2H, s), 7.76 (2H, d), 7.88 (2H, d)
Process 4
N- [2- (5-Amidino-2-methylphenoxy) ethyl] -4-amidinobenzamide Synthesis of ditrifluoroacetate
Starting from 2.00 g (6.55 mmol) of N- [2- (5-cyano-2-methylphenoxy) ethyl] -4-cyanobenzamide, the title compound was obtained in the same manner as in Step 5 of Example 95. It was.
Yield 914 mg (1.61 mmol) Yield 25%
MS (ESI, m / z) 340 (MH +)
H-NMR (DMSO-d6) δ2.23 (3H, s), 3.73 (2H, d), 4.26 (2H, t), 7.36 (1H, d), 7.37 (1H, s), 7.41 (1H, d ), 7.90 (2H, d), 8.05 (2H, d), 8.93 (2H, br), 9.02 (1H, br), 9.11 (2H, br), 9.24 (2H, br), 9.41 (2H, br) ,
Example 149
N- [5-Amidino-2- [2- (2-furyl) -2-oxoethyl] phenoxy] ethyl-4-amidinobenzamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of N- [2- (5-cyano-2-bromomethylphenoxy) ethyl] -4-cyanobenzamide
12.0 g (39.3 mmol) of N- [2- (5-cyano-2-methylphenoxy) ethyl] -4-cyanobenzamide was dissolved in 200 ml of carbon tetrachloride, and 7.00 g (39.3 mmol) of N-bromosuccinimide was dissolved. ), 700 mg (4.26 mmol) of azoisobutyronitrile was added. After stirring at 100 ° C. for 3 days, 16.8 g (94.4 mmol) of N-bromosuccinimide and 2.1 g (12.8 mmol) of azoisobutyronitrile were further added and stirred for 2 days. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 11.96 g (31.2 mmol) Yield 79%
MS (FAB, m / z) 384 (MH +)
H-NMR (CDCl3) δ 4.00 (2H, dd), 4.30 (2H, t), 4.55 (2H, s), 7.14 (1H, d), 7.26 (1H, dd), 7.42 (1H, d), 7.72 (2H, d), 7.82 (2H, d)
Process 2
N- [5-Amidino-2- [2- (2-furyl) -2-oxoethyl] phenoxy] ethyl-4-amidinobenzamide Synthesis of ditrifluoroacetate
Tetrakistriphenylphosphine palladium (230 mg, 0.20 mmol) and powdered zinc (85 mg, 1.30 mmol) were added with 5 ml of acetonitrile and 0.2 ml (2.0 mmol) of 2-furoyl chloride in an argon atmosphere. 383 mg (1.0 mmol) of dissolved N- [2- (5-cyano-2-bromomethylphenoxy) ethyl] -4-cyanobenzamide was added at room temperature and stirred as it was for 24 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography, and the title compound was obtained from the obtained compound in the same manner as in Step 5 of Example 95.
Yield 6.6 mg (0.010 mmol) Yield 1.0%
MS (ESI, m / z) 434 (MH +)
H-NMR (DMSO-d6) δ 3.58 (2H, dd), 4.19 (2H, t), 4.28 (2H, s), 6.68 (1H, dd), 7.38-7.41 (1H, m), 7.42 (1H , d), 7.43 (1H, s), 7.48 (1H, dd), 7.88 (2H, d), 7.96 (2H, d), 7.99-8.05 (1H, m), 8.80 (1H, t), 9.13 ( 2H, br), 9.28 (4H, br), 9.41 (2H, br)
keto form 100%
Example 150
Synthesis of 3-[(2S) -2-amino-3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine tritrifluoroacetate
3-[(2S) -2-Amino-3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
Process 1
Synthesis of benzyl 4-hydroxypiperidine-1-carboxylate
4-Hydroxypiperidine (25.0 g, 247 mmol) was dissolved in dichloromethane (800 ml), and carbobenzyloxychloride (38 ml, 266 mmol) and triethylamine (75 ml, 538 mmol) were added at 0 ° C., followed by stirring at room temperature for 15 hours. Treatment was performed according to a conventional method using dichloromethane as an extraction solvent to obtain an oily residue. This was used in the next reaction without purification.
Yield 44.6 g (203 mmol) Yield 82%
Process 2
Synthesis of methyl (2S) -2- (t-butoxycarbonylamino) -3- (4-hydroxyphenyl) propionate
L-tyrosine methyl ester hydrochloride 15.2 g (65.6 mmol) is dissolved in 200 ml of dichloromethane, and 20 ml (143 mmol) of triethylamine and 13.1 g (60.0 mmol) of di-t-butyl dicarbonate are dissolved in 50 ml of dichloromethane at room temperature. Was added and stirred for 15 hours. Using dichloromethane as an extraction solvent, an oily residue was obtained by the same isolation procedure as in Step 1 of Example 1. This was used in the next reaction without purification.
Yield 19.2 g (65.2 mmol) Yield 99%
Process 3
Synthesis of methyl (2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propionate
18.9 g (86.2 mmol) of benzyl 4-hydroxypiperidine-1-carboxylate, 25.4 g of methyl (2S) -2- (t-butoxycarbonylamino) -3- (4-hydroxyphenyl) propionate (86. 2 mmol) and 27.1 g (103.4 mmol) of triphenylphosphine were dissolved in 500 ml of tetrahydrofuran, and 37.5 g (86.2 mmol) of diethyl azodicarboxylate was added at room temperature, followed by stirring for 15 hours. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 32.1 g (62.6 mmol) Yield 73%
H-NMR (CDCl3) δ1.42 (9H, s), 1.70-1.84 (2H, m), 1.86-2.00 (2H, m), 2.91-3.10 (2H, m), 3.38-3.53 (2H, m) , 3.70 (3H, s), 3.71-3.82 (2H, m), 4.40-4.44 (1H, m) 4.45-4.60 (1H, m), 4.93-5.00 (1H, m), 5.18 (2H, s), 6.92 (2H, d), 7.02 (2H, d), 7.13-7.21 (5H, m)
Process 4
Synthesis of benzyl 4- [4-[(2S) -2- (t-butoxycarbonylamino) -3-hydroxypropyl] phenoxy] piperidine-1-carboxylate
30 ml of tetrahydrofuran (10.4 g, 20.3 mmol) of (2S) -3- [4- [1- [benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propionate, Dissolve in 30 ml of methanol, add 2.44 g (64.5 mmol) of sodium borohydride at 0 ° C., return to room temperature and stir for 15 hours, then again add 0.82 g (21.7 mmol) of sodium borohydride at 0 ° C. In addition, the mixture was returned to room temperature and further stirred for 2 hours. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 9.45 g (19.5 mmol) Yield 96%
H-NMR (CDCl3) δ 1.44 (9H, s), 1.68-1.82 (2H, m), 1.84-1.98 (2H, m), 2.78 (2H, d), 3.29-3.95 (7H, m), 4.40 -4.44 (1H, m), 5.14 (2H, s), 6.92 (2H, d), 7.12 (2H, d), 7.28-7.40 (5H, m)
Process 5
Synthesis of benzyl 4- [4-[(2S) -3-chloro-2- (t-butoxycarbonylamino) propyl] phenoxy] piperidine-1-carboxylate
4- [4-[(2S) -2- (t-butoxycarbonylamino) -3-hydroxypropyl] phenoxy] piperidine-1-carboxylate 5.5 g (11.3 mmol) was dissolved in dichloromethane 60 ml. At 0 ° C., 3.2 ml (22.6 mmol) of triethylamine and 1.95 g (17.0 mmol) of methanesulfonyl chloride were added. After stirring for 4 hours, dichloromethane was used as an extraction solvent, and the mixture was treated by the same isolation procedure as in Step 1 of Example 1 to obtain an oily residue. The residue thus obtained was dissolved in 120 ml of dimethylformamide, 2.57 g (60.6 mmol) of lithium chloride was added, and the mixture was stirred at 50 ° C. for 15 hours. Ethyl acetate was used as an extraction solvent, and the product was treated by the same isolation operation as in Step 1 of Example 1 to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 2.60 g (5.16 mmol) Yield 45%
H-NMR (CDCl3) δ1.44 (9H, s), 1.63-1.82 (2H, m), 1.83-2.00 (2H, m), 2.91-3.10 (2H, m), 2.83 (2H, d), 3.40 -3.54 (3H, m), 3.57-3.63 (1H, m), 3.66-3.80 (3H, m), 4.40-4.52 (1H, m), 5.14 (2H, s), 6.92 (2H, d), 7.16 (2H, d), 7.13-7.21 (5H, m)
Step 6
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile
6.4 g (12.7 mmol) of benzyl 4- [4-[(2S) -3-chloro-2- (t-butoxycarbonylamino) propyl] phenoxy] piperidine-1-carboxylate was dissolved in 70 ml of dimethylformamide, 2.27 g (19.1 mmol) of 3-cyanophenol and 3.51 g (25.4 mmol) of potassium carbonate were added and stirred at 70 ° C. for 15 hours. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 5.0 g (8.54 mmol) Yield 67%
H-NMR (CDCl3) δ1.44 (9H, s), 1.66-1.83 (2H, m), 1.84-2.00 (2H, m), 2.50-2.60 (1H, m), 2.82-2.93 (1H, m) , 3.40-3.53 (3H, m), 3.58-3.63 (1H, m), 3.65-3.80 (3H, m), 4.40-4.53 (1H, m), 5.14 (2H, s) 6.92 (2H, d), 7.16 (2H, d), 7.13-7.21 (5H, m)
Step 7
Synthesis of 3-[(2S) -2-amino-3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine tritrifluoroacetate
3-[(2S) -2-Amino-3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile hydrochloride 10 mg (0.0171 mmol) Was added with 5 ml of ethanol containing 30% hydrogen chloride (W / V) and stirred at room temperature for 24 hours. Subsequently, the solution was dissolved in 10 ml of an ethanol solution containing 30% ammonia (W / V) at room temperature and stirred at room temperature for 24 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction. 3-[(2S) -2-amino-3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine tritrifluoroacetate:
Yield 2.2 mg (0.0031 mmol) Yield 18.1%
MS (FAB, m / z) 369 (MH +)
H-NMR (DMSO-d6) δ 1.65-1.85 (2H, m), 2.00-2.10 (2H, m), 2.82-3.60 (6H, m), 3.60-3.90 (1H, m), 3.93-4.01 ( 1H, m), 4.10-4.20 (1H, m), 4.58-4.62 (1H, m), 6.75 (2H, d), 6.98 (2H, d), 7.20-7.60 (4H, m), 8.10 (3H, br), 8.55 (2H, br), 9.08 (2H, br), 9.30 (2H, br) 3-[(2S) -2-amino-3- [4- [1- (benzyloxycarbonyl) -4- Piperidyloxy] phenyl] propoxy] benzamidine ditrifluoroacetate:
Yield 3.2 mg (0.00438 mmol) Yield 25.6%
MS (ESI, m / z) 503 (MH +)
H-NMR (DMSO-d6) δ 1.42-1.61 (2H, m), 1.83-1.97 (2H, m), 2.89-2.99 (2H, m), 3.20-3.62 (3H, m), 3.65-3.89 ( 2H, m), 3.95-4.05 (1H, m), 4.11-4.20 (1H, m), 4.50-4.60 (1H, m), 5.08 (2H, s), 6.98 (2H, d), 7.20 (2H, d), 7.30-7.60 (9H, m), 8.10 (3H, br), 9.05 (2H, br), 9.35 (2H, br)
Example 151
Synthesis of 3-[(2R) -2-amino-3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine tritrifluoroacetate
Synthesis of 3-[(2R) -2-amino-3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propoxy] benzamidine ditrifluoroacetate
3-[(2R) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile hydrochloride 39.4 mg (0. (0657 mmol) was added with 10 ml of ethanol (W / V) containing 30% hydrogen chloride, and the mixture was stirred at room temperature for 24 hours. Subsequently, the mixture was dissolved in 10 ml of an ethanol solution containing 10% ammonia (W / V) at room temperature and stirred at room temperature for 24 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
3-[(2R) -2-amino-3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine tritrifluoroacetate:
Yield 2.4 mg (0.00338 mmol) Yield 5.05%
MS (ESI, m / z) 369 (MH +)
H-NMR (DMSO-d6) δ 1.65-1.82 (2H, m), 1.95-2.11 (2H, m), 2.61-2.85 (2H, m), 3.02-4.10 (7H, m), 4.52-4.64 ( 1H, m), 6.70 (2H, d), 7.02 (2H, d), 7.20-7.35 (5H, m), 7.28-7.48 (3H, m), 7.55 (1H, t), 8.37 (3H, br) , 9.22 (2H, d), 9.32 (2H, br), 9.47 (2H, br)
3-[(2R) -2-amino-3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propoxy] benzamidine ditrifluoroacetate:
Yield 3.2 mg (0.00438 mmol) Yield 5.53%
MS (ESI, m / z) 503 (MH +)
H-NMR (DMSO-d6) δ 1.47-1.61 (2H, m), 1.85-1.96 (2H, m), 2.90-3.01 (2H, m), 3.20-3.35 (2H, m), 3.67-3.87 ( 2H, m), 3.95-4.05 (1H, m), 4.12-4.18 (1H, m), 5.08 (2H, s), 6.95 (2H, d), 7.20 (2H, d), 7.30-7.45 (8H, m), 7.57 (1H, t), 8.21 (3H, br), 9.18 (2H, br), 9.31 (2H, br)
Example 152
3-[(2S) -2- (ethanesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
Synthesis of 3-[(2S) -2- (ethanesulfonylamino) -3- [4- (ethanesulfonyloxy) phenyl] propoxy] benzamidine trifluoroacetate
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (ethanesulfonylamino) propoxy] benzamidine trifluoroacetate
3-[(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile hydrochloride 25 mg (0.0479 mmol) Then, 72.6 mg (0.735 mmol) of triethylamine was dissolved in 5 ml of DMF, and 21.3 mg (0.166 mmol) of ethanesulfonyl chloride was added at room temperature, followed by stirring at room temperature overnight. Using ethyl acetate as an extraction solvent, an oily residue was obtained by the same isolation procedure as in Step 1 of Example 1. Subsequently, the title compound was obtained in the same manner as the Example 150. 3-[(2S) -2- (ethanesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine ditrifluoroacetate:
Yield 4.8 mg (0.00697 mmol) Yield 14.6%
MS (ESI, m / z) 461 (MH +)
H-NMR (DMSO-d6) δ0.93 (3H, t), 1.68-1.82 (2H, m), 1.98-2.18 (2H, m), 2.58 (2H, q), 2.62-3.02 (2H, m) , 3.02-3.50 (5H, m), 4.00 (2H, d), 4.55-4.62 (1H, m), 6.97 (2H, d), 7.22 (2H, d), 7.27-7.60 (4H, m), 8.21 (1H, br), 8.35 (2H, br), 9.10 (2H, br), 9.38 (2H, br) 3-[(2S) -2- (ethanesulfonylamino) -3- [4- (ethanesulfonyloxy) ) Phenyl] propoxy] benzamidine trifluoroacetate:
Yield 1.6 mg (0.00274 mmol) Yield 5.9%
MS (ESI, m / z) 470 (MH +)
H-NMR (DMSO-d6) δ 0.88 (3H, t), 1.38 (3H, t), 2.52-3.10 (4H, m), 3.46 (2H, q), 3.78-3.86 (1H, m), 4.15 (2H, t), 7.27 (2H, d), 7.30-7.40 (2H, m), 7.43 (2H, d), 7.46-7.58 (2H, m), 7.43 (2H, d), 7.46-7.58 (2H , m), 8.95 (2H, br), 9.32 (2H, br)
3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (ethanesulfonylamino) propoxy] benzamidine trifluoroacetic acid: Yield 2.8 mg (0. 00395 mmol) Yield 8.14%
MS (ESI, m / z) 595 (MH +)
H-NMR (DMSO-d6) δ 0.93 (3H, t), 1.47-1.61 (2H, m), 1.85-1.96 (2H, m), 2.90-3.01 (2H, m), 3.20-3.35 (2H, m), 3.67-3.87 (2H, m), 3.95-4.05 (1H, m), 4.12-4.18 (1H, m), 5.08 (2H, s), 6.95 (2H, d), 7.20 (2H, d) , 7.30-7.45 (8H, m), 7.57 (1H, t), 8.21 (3H, br), 9.18 (2H, br), 9.31 (2H, br)
Example 153
3-[(2S) -2- (butanesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
Synthesis of 3-[(2S) -2- (butanesulfonylamino) -3- [4- (butanesulfonyloxy) phenyl] propoxy] benzamidine trifluoroacetic acid
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (butanesulfonylamino) propoxy] benzamidine trifluoroacetate
3-[(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile hydrochloride 25 mg (0.0479 mmol) Then, 72.6 mg (0.735 mmol) of triethylamine was dissolved in 5 ml of DMF, and 20.0 mg (0.128 mmol) of butanesulfonyl chloride was added at room temperature, followed by stirring at room temperature overnight. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. Subsequently, the title compound was obtained in the same manner as the Example 150.
3-[(2S) -2- (butanesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine ditrifluoroacetate:
Yield 2.0 mg (0.00279 mmol) Yield 5.80%
MS (ESI, m / z) 489 (MH +)
H-NMR (DMSO-d6) δ0.82 (3H, t), 1.08-1.42 (4H, m), 1.70-1.84 (2H, m), 1.95-2.13 (2H, m), 2.58 (2H, t) 2.60-3.10 (2H, m), 3.20-3.58 (4H, m), 3.62-3.82 (1H, m), 3.92-4.10 (2H, m), 4.56-4.65 (1H, m), 5.08 (2H, s), 6.92 (2H, d), 7.24 (2H, d), 7.30-7.58 (4H, m), 8.10 (1H, m), 8.26 (2H, br), 9.05 (2H, br), 9.26 (2H) , br)
3-[(2S) -2- (butanesulfonylamino) -3- [4- (butanesulfonyloxy) phenyl] propoxy] benzamidine trifluoroacetic acid:
Yield 2.9 mg (0.00453 mmol) Yield 9.54%
MS (ESI, m / z) 526 (MH +)
H-NMR (DMSO-d6) δ 0.76 (3H, t), 0.92 (3H, t), 1.10-1.82 (10H, m), 2.52-2.70 (4H, m), 2.71-3.10 (2H, m) , 3.42-3.58 (2H, m), 3.76-3.88 (1H, m), 4.00-4.18 (2H, m), 7.20-7.60 (8H, m), 8.92 (2H, br), 9.28 (2H, br)
3-[(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (butanesulfonylamino) propoxy] benzamidine trifluoroacetate: Yield 2.8 mg (0 .00380 mmol) Yield 8.00%
MS (ESI, m / z) 623 (MH +)
H-NMR (DMSO-d6) δ0.93 (3H, t), 1.25-1.98 (4H, m), 2.58 (2H, t), 2.62-3.00 (2H, m), 3.62-3.80 (3H, m) , 3.95-4.12 (2H, m), 4.28-4.32 (2H, m), 4.48-4.60 (1H, m), 5.08 (2H, s), 6.92 (2H, d), 7.22 (2H, d), 7.30 -7.46 (8H, m), 7.52-7.58 (1H, m), 8.97 (2H, br), 9.29 (2H, br)
Example 154
3-[(2S) -2- (Benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (benzenesulfonylamino) propoxy] benzamidine trifluoroacetate
3-[(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile hydrochloride 25 mg (0.0479 mmol) 72.6 mg (0.735 mmol) of triethylamine was dissolved in 5 ml of DMF, and 20.0 mg (0.113 mmol) of butanesulfonyl chloride was added at room temperature, followed by stirring at room temperature overnight. Using ethyl acetate as an extraction solvent, an oily residue was obtained by the same isolation procedure as in Step 1 of Example 1. Subsequently, the title compound was obtained in the same manner as the Example 150.
3-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine ditrifluoroacetate:
Yield 3.7 mg (0.00502 mmol) Yield 10.5%
MS (ESI, m / z) 509 (MH +)
H-NMR (DMSO-d6) δ1.76-1.90 (2H, m), 2.03-2.17 (2H, m), 2.62 (1H, dd), 2.83 (1H, dd), 3.00-3.39 (4H, m) , 3.58-3.64 (1H, m), 3.94 (2H, d), 4.52-4.64 (1H, m), 6.79 (2H, d), 7.01 (2H, d), 7.08-7.56 (7H, m), 7.64 -7.70 (2H, m), 8.12 (1H, d), 9.14 (2H, br), 9.33 (2H, br), 9.38 (2H, br)
3-[(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (benzenesulfonylamino) propoxy] benzamidine trifluoroacetate:
Yield 2.8 mg (0.00370 mmol) Yield 7.79%
MS (ESI, m / z) 643 (MH +)
H-NMR (DMSO-d6) δ 1.42-1.60 (2H, m), 1.86-1.97 (2H, m), 2.68 (1H, dd), 2.80 (1H, dd), 3.20-3.58 (2H, m) , 3.58-3.64 (1H, m), 3.64-3.80 (2H, m), 3.94 (2H, d), 4.40-4.53 (1H, m), 5.06 (2H, s), 6.76 (2H, d), 6.96 (2H, d), 7.10-7.24 (2H, m), 7.32-7.54 (10H, m), 7.62-7.70 (2H, m), 8.08 (1H, d), 8.94 (2H, br), 9.26 (2H , br)
Example 155
Synthesis of 3-[(2S) -2- (2-naphthalenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine ditrifluoroacetate
Synthesis of 3-[(2S) -2- (butanesulfonylamino) -3- (4-hydroxyphenyl) propoxy] benzamidine trifluoroacetic acid
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (2-naphthalenesulfonylamino) propoxy] benzamidine trifluoroacetate
3-[(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile hydrochloride 25 mg (0.0479 mmol) Then, 72.6 mg (0.735 mmol) of triethylamine was dissolved in 5 ml of DMF, 20.0 mg (0.0882 mmol) of 2-naphthalenesulfonyl chloride was added at room temperature, and the mixture was stirred at room temperature overnight. Using ethyl acetate as an extraction solvent, an oily residue was obtained by the same isolation procedure as in Step 1 of Example 1. Subsequently, the title compound was obtained in the same manner as the Example 150.
3-[(2S) -2- (2-naphthalenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine ditrifluoroacetate:
Yield 5.5 mg (0.00699 mmol) Yield 14.7%
MS (ESI, m / z) 559 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.91 (2H, m), 2.00-2.12 (2H, m), 2.62 (1H, dd), 2.82 (1H, dd), 2.94-3.24 (4H, m) , 3.64-3.76 (1H, m), 3.95 (2H, d), 4.38-4.48 (1H, m), 6.65 (2H, d), 6.97 (2H, d), 6.92-7.04 (1H, m), 7.10 -7.55 (5H, m), 7.60-7.70 (3H, m), 7.82 (1H, d), 7.92 (1H, d), 8.08 (1H, d), 8.22 (1H, d), 8.31 (1H, s ), 9.17 (2H, br), 9.29 (2H, br), 9.34 (2H, br)
3-[(2S) -2- (butanesulfonylamino) -3- (4-hydroxyphenyl) propoxy] benzamidine trifluoroacetic acid:
Yield 2.1 mg (0.00356 mmol) Yield 7.52%
MS (ESI, m / z) 476 (MH +)
H-NMR (DMSO-d6) δ2.58 (1H, dd), 2.76 (1H, dd), 3.60-3.70 (1H, m), 3.86 (2H, d), 6.49 (2H, d), 6.84 (2H , d), 6.94-7.02 (1H, m), 7.08 (1H, s), 7.29 (1H, d), 7.37 (1H, dd), 7.60-8.00 (8H, m), 8.08 (1H, d), 8.14 (1H, d), 8.94 (2H, br), 9.13 (1H, s), 9.20 (2H, br) 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4- Piperidyloxy] phenyl] -2- (2-naphthalenesulfonylamino) propoxy] benzamidine trifluoroacetate:
Yield 2.7 mg (0.00335 mmol) Yield 14.7%
MS (ESI, m / z) 693 (MH +)
H-NMR (DMSO-d6) δ 1.40-1.58 (2H, m), 1.78-1.92 (2H, m), 2.60 (1H, dd), 2.80 (1H, dd), 3.20-3.40 (2H, m) , 3.62-3.86 (3H, m), 3.95 (2H, d), 4.25-4.38 (1H, m), 5.07 (2H, s), 6.60 (2H, d), 6.93 (2H, d), 7.04-7.08 (1H, m), 7.14-7.18 (1H, m), 7.28-7.40 (9H, m), 7.58-7.64 (3H, m), 7.91 (1H, d), 7.94 (1H, d), 8.05 (1H , d), 8.16 (1H, d), 8.30 (1H, s), 8.90 (2H, br), 9.21 (2H, br)
Example 157
3-[(2R) -2- (ethanesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile trifluoroacetate 11 mg (0. 0183 mmol) and 72.6 mg (0.735 mmol) of triethylamine were dissolved in 5 ml of DMF, and 10.0 mg (0.166 mmol) of ethanesulfonyl chloride was added at room temperature, followed by stirring at room temperature overnight. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. Subsequently, the title compound was obtained in the same manner as the Example 150.
Yield 1.76 mg (0.00256 mmol) Yield 14.0%
MS (ESI, m / z) 461 (MH +)
H-NMR (DMSO-d6) δ0.94 (3H, t), 1.68-1.83 (2H, m), 2.00-2.16 (2H, m), 2.58 (2H, q), 2.70 (1H, dd), 2.95 (1H, dd), 2.98-3.38 (4H, m), 3.68-3.81 (1H, m), 4.01-4.04 (2H, m), 4.58-4.61 (1H, m), 6.95 (2H, m), 7.25 (2H, m), 7.40-7.60 (4H, m), 8.42 (2H, br), 8.90 (2H, br), 9.11 (2H, br)
Example 157
3-[(2R) -2- (Benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile trifluoroacetate 11 mg (0. 0183 mmol) and 4.3 mg (0.10 mmol) of pyridine were dissolved in 2.5 ml of DMF, and 4.3 mg (0.0245 mmol) of benzenesulfonyl chloride was added at room temperature, followed by stirring at room temperature overnight. Using ethyl acetate as an extraction solvent, an oily residue was obtained by the same isolation procedure as in Step 1 of Example 1. Subsequently, the title compound was obtained in the same manner as the Example 150.
Yield 1.58 mg (0.00214 mmol) Yield 11.7%
MS (ESI, m / z) 509 (MH +)
H-NMR (DMSO-d6) δ 1.56-1.71 (2H, m), 1.84-2.01 (2H, m), 2.69-2.96 (3H, m), 3.19-3.28 (2H, m), 3.42-3.57 ( 1H, m), 3.71-3.81 (1H, m), 3.94-4.02 (1H, m), 4.04-4.18 (1H, m), 4.26-4.41 (1H, m), 6.86 (2H, d), 7.13 ( 2H, d), 7.28-7.81 (9H, m), 8.12 (1H, d), 8.14 (2H, br), 9.01 (2H, br), 9.29 (2H, br)
Example 158
3-[(2S) -2- (Benzenesulfonylamino) -3- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate 3-[(2S) 2- (Benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine 20 mg (0.0271 mmol) ditrifluoroacetate and 2.18 mg (2.15 mmol) triethylamine in 5 ml ethanol After dissolution, 10.0 mg (0.0809 mmol) of ethylacetoimidate hydrochloride was added at room temperature, and the mixture was stirred at room temperature overnight. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 13.2 mg (0.00169 mmol) Yield 62.6%
MS (ESI, m / z) 550 (MH +)
H-NMR (DMSO-d6) δ 1.63-1.82 (2H, m), 1.97-2.17 (2H, m), 2.29 (3H, s), 2.60 (1H, dd), 2.81 (1H, dd), 3.42 -3.81 (5H, m), 3.86 (2H, d), 4.58-4.64 (1H, m), 6.78 (2H, d), 7.01 (2H, d), 7.11-7.68 (9H, m), 8.09 (1H , d), 8.58 (1H, s), 9.04 (2H, br), 9.11 (1H, br), 9.27 (2H, br)
Example 159
3-[(2S) -2- (Benzenesulfonylamino) -3- [4- (1-amidino-4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
3-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine 20 mg (0.0271 mmol) ditrifluoroacetate, 72 mg (2.15 mmol) triethylamine Was dissolved in 2 ml of DMF, and 20.0 mg (0.185 mmol) of amidinesulfinic acid was added at room temperature, followed by stirring at room temperature overnight. Purification in the same manner as in Example 150 was performed to obtain the title compound.
Yield 8.4 mg (0.0108 mmol) Yield 39.8%
MS (ESI, m / z) 551 (MH +)
H-NMR (DMSO-d6) δ 1.58-1.68 (2H, m), 1.89-1.96 (2H, m), 2.54-2.62 (1H, m), 2.68-2.97 (3H, m), 3.21-3.42 ( 2H, m), 3.54-3.68 (1H, m), 3.92 (2H, d), 4.30-4.41 (1H, m), 6.73 (2H, d), 6.92 (2H, d), 7.05-7.72 (9H, m), 8.08 (1H, d), 8.90 (4H, br), 9.21 (4H, br)
Example 160
3-[(2S) -2- (ethanesulfonylamino) -3- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile 1.19 g (1.99 mmol) of hydrochloride as a starting material The crude product was obtained by the same operation as in Example 158 without performing the same operation as in Example 152 and purifying the resulting intermediate. Thereafter, the same purification as in Example 150 was performed to obtain the title compound.
Yield 63 mg (0.086 mmol) Yield 4.3%
MS (ESI, m / z) 502 (MH +)
H-NMR (D2O) δ1.05 (3H, t), 1.82-1.97 (2H, m), 2.07-2.17 (2H, m), 2.37 (3H, s), 2.62-3.21 (4H, m), 3.47 -3.96 (5H, m), 4.06-4.20 (2H, m), 4.67-4.73 (1H, m), 7.18 (2H, d), 7.29 (2H, d), 7.30-7.61 (4H, m)
Example 161
3-[(2S) -2- (Butanesulfonylamino) -3- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile 1.19 g (1.99 mmol) of hydrochloride as a starting material The crude product was obtained in the same manner as in Example 158 without performing the same operation as in Example 153 and purifying the resulting intermediate. Thereafter, the same purification as in Example 150 was performed to obtain the title compound.
Yield 11.8 mg (0.234 mmol) Yield 11.8%
MS (ESI, m / z) 530 (MH +)
H-NMR (DMSO-d6) δ 0.89 (3H, t), 1.10-1.50 (4H, m), 1.71-1.90 (2H, m), 1.98-2.12 (2H, m), 2.28-2.56 (2H, q), 2.60-2.98 (2H, m), 3.52-3.60 (2H, m), 3.62-3.92 (3H, m), 3.98-4.07 (2H, m), 4.58-4.69 (1H, m), 6.92 ( 2H, d), 7.21 (2H, d), 7.24-7.61 (4H, m), 8.57 (1H, br), 9.05 (1H, br), 9.22 (2H, br), 9.28 (2H, br)
Example 162
Synthesis of 3-[(2S) -2- (2-naphthalenesulfonylamino) -3- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] propoxy] benzamidine ditrifluoroacetate
3-[(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile hydrochloride 1.19 g (1. 99 mmol) as a starting material, the same operation as in Example 155 was performed, and the crude product was obtained by the same operation as in Example 158 without purifying the resulting intermediate. Thereafter, the same purification as in Example 150 was performed to obtain the title compound.
Yield 36 mg (0.0435 mmol) Yield 2.2%
MS (ESI, m / z) 600 (MH +)
H-NMR (DMSO-d6) δ 1.60-1.79 (2H, m), 1.90-2.08 (2H, m), 2.25 (3H, s), 2.58-2.92 (2H, s), 3.41-3.58 (2H, m), 3.60-3.91 (3H, m), 3.96 (2H, d), 4.41-4.57 (1H, m), 6.67 (2H, d), 6.98 (2H, d), 7.04 (1H, d), 7.15 (1H, s), 7.34 (1H, d), 7.41 (1H, dd), 7.60-7.78 (5H, m), 7.92 (1H, d), 7.97 (1H, d), 8.01 (1H, d), 8.17 (1H, d), 8.30 (1H, s)
Example 163
3- [3- [4-[(3S) -1-acetimidoyl-3-pyrrolidyloxy] phenyl] -2- (benzenesulfonylamino) propoxy] benzamidine Synthesis of ditrifluoroacetate salt (3S) -3 Benzyl-hydroxypyrrolidine-1-carboxylate, 2S) -2- (t-butoxycarbonylamino) -3- (4-hydroxyphenyl) propionate as a starting material, Example 154, then Example 158 The same operation was performed to obtain the title compound.
MS (ESI, m / z) 536 (MH +)
H-NMR (DMSO-d6) A 1: 1 mixture of geometric isomers A and B of acetimidoyl moiety δ1.90-2.05 (2H, m), 1.99 (3H, s, for A), 2.03 (3H, s, for B), 2.35 (1H, dd), 2.58 (1H, dd), 3, 15-3.60 (6H, m), 3.67 (2H, m), 4.87 (1H, d), 6.50 (2H, dd ), 6.76 (2H, d), 6.86 (1H, dd), 6.96 (1H, br), 7.10-7.28 (4H, m), 7.40 (2H, d), 7.82 (1H, d), 8.10 (1H, s, for A), 8.18 (1H, s, for A), 8.80 (1H, s, for B), 8.87 (1H, s, for B), 8.88 (2H, s), 9.01 (2H, s)
Example 164
3-[(2S) -2- (Benzenesulfonylamino) -3- [4- (4-piperidylmethyl) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
Process 1
Synthesis of (2S) -3- [4-[(1-acetyl-4-piperidyl) hydroxymethyl] phenyl] -2- (benzenesulfonylamino) propanol
6.32 g (19.8 mmol) of methyl (2S) -2- (benzenesulfonylamino) -3-phenylpropionate and 3.88 g (20.4 mmol) of N-acetylisonipecotic chloride were suspended in 60 ml of dichloromethane. After adding 13.6 g (102.0 mmol) of aluminum chloride, the mixture was stirred at room temperature overnight. Using dichloromethane as an extraction solvent, an oily residue was obtained by the same isolation procedure as in Step 1 of Example 1. Subsequently, the mixture was dissolved in a mixed solvent of 30 ml of ethanol and 50 ml of methanol, 1.68 g (44.4 mmol) of sodium borohydride was added, and the mixture was stirred overnight. The title compound was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent.
Yield 2.11 g (4.73 mmol) Yield 23.9%
MS (ESI, m / z) 469 (MNa +)
Process 2
Synthesis of 4- [4-[(2S) -3-acetoxy-2- (benzenesulfonylamino) propyl] phenyl] methyl] piperidine
2.11 g (4.73 mmol) of (2S) -3- [4-[(1-acetyl-4-piperidyl) hydroxymethyl] phenyl] -2- (benzenesulfonylamino) propanol was added to 20 ml of 4N hydrogen chloride and 40 ml of ethanol. Dissolved and stirred at 95 ° C. overnight. The residue obtained by distilling off the solvent was added with 100 mg of 10% palladium carbon, 0.5 ml of concentrated sulfuric acid and 20 ml of acetic acid, and reduction was carried out in a hydrogen atmosphere at 50 ° C. and 4 atm. The solvent was distilled off to give the title crude.
Yield 291 mg (0.675 mmol) Yield 14.3%
Process 3
Synthesis of t-butyl 4- [4-[(2S) -3-acetoxy-2- (benzenesulfonylamino) propyl] phenyl] methyl] piperidine-1-carboxylate
4- [4-[(2S) -3-acetoxy-2- (benzenesulfonylamino) propyl] phenyl] methyl] piperidine 291 mg (0.675 mmol), di-t-butyl dicarbonate 151 mg (0.693 mmol), triethylamine 726 mg (7.17 mmol) was dissolved in 20 ml of dichloromethane and stirred overnight. After distilling off the solvent, 0.5 ml of 1N sodium hydroxide aqueous solution and 40 ml of methanol were added and reacted at 40 ° C. overnight. The residue obtained by distilling off the solvent was subjected to reversed-phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, eluting with a mixed solvent of water and acetonitrile, and the fraction of interest was distilled under reduced pressure. The title compound was obtained by leaving.
Yield 168 mg (0.344 mmol) Yield 51.0%
MS (ESI, m / z) 489 (MH +)
Process 4
Synthesis of t-butyl 4- [4-[(2S) -2- (benzenesulfonylamino) -3-methanesulfonyloxypropyl] phenyl] methyl] piperidine-1-carboxylate
4- [4-[(2S) -3-acetoxy-2- (benzenesulfonylamino) propyl] phenyl] methyl] piperidine-1-carboxylate 168 mg (0.344 mmol), triethylamine 500 mg (4.94 mmol) Was dissolved in 15 ml of dichloromethane, cooled with ice, and 100 mg (0.873 mmol) of methanesulfonyl chloride was stirred for 3 hours. The title crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent.
Yield 139 mg (0.245 mmol) Yield 71.2%
MS (ESI, m / z) 567 (MH +)
H-NMR (CDCl3) δ1.03-1.90 (5H, m), 1.42 (9H, s), 2.43 (2H, d), 2.60-2.84 (2H, m), 3.15 (3H, s), 3.60-3.71 (1H, m), 3.98-4.21 (6H, m), 6.92 (2H, d), 6.97 (2H, d), 7.41-7.77 (5H, m)
Process 5
Synthesis of t-butyl 4-[[4-[(2S) -2- (benzenesulfonylamino) -3-chloropropyl] phenyl] methyl] piperidine-1-carboxylate
4- [4-[(2S) -2- (benzenesulfonylamino) -3-methanesulfonyloxypropyl] phenyl] methyl] piperidine-1-carboxylate 139 mg (0.245 mmol), lithium chloride 500 mg (11 0.7 mmol) was dissolved in 15 ml of DMF and stirred at 50 ° C. for 6 hours. The title crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent.
Yield 94.8 mg (0.187 mmol) Yield 76.3%
MS (ESI, m / z) 508 (MH +)
H-NMR (CDCl3) δ 1.03-1.80 (5H, m), 1.42 (9H, s), 2.45 (2H, d), 2.60-2.84 (2H, m), 3.10 (3H, s), 3.47 (2H , d), 3.64-3.80 (1H, m), 4.01-4.18 (4H, m), 6.94-7.00 (4H, m), 7.40-7.82 (5H, m)
Step 6
Synthesis of 3- [2- (benzenesulfonamino) -3- [4-[[1- (t-butoxycarbonylamino) piperidyl] methyl] phenyl] propoxy] benzamidine
4-[[4-[(2S) -2- (benzenesulfonylamino) -3-chloropropyl] phenyl] methyl] piperidine-1-carboxylate 94.8 mg (0.187 mmol), 3-cyanophenol 275 mg (2.31 mmol) and 385 mg (2.79 mmol) of potassium carbonate were dissolved in 15 ml of DMF and stirred at 75 ° C. for 60 hours. The title compound was obtained by performing the same operation as in Example 150 on the oily residue obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as the extraction solvent.
Yield 87.5 mg (0.0148 mmol) Yield 79.1%
MS (ESI, m / z) 590 (MH +)
H-NMR (CDCl3) δ 1.03-1.79 (5H, m), 1.42 (9H, s), 2.24 (2H, d), 2.48-2.92 (2H, m), 3.68-3.91 (2H, m), 3.92 (2H, d), 3.98-4.10 (2H, m), 4.27-4.38 (1H, m), 6.91 (2H, d), 6.98 (2H, d), 7.28-7.91 (9H, m)
Step 7
3-[(2S) -2- (Benzenesulfonylamino) -3- [4- (4-piperidylmethyl) phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate
Example 150 with 3- [2- (benzenesulfonamino) -3- [4-[[1- (t-butoxycarbonylamino) piperidyl] methyl] phenyl] propoxy] benzamidine 43.8 mg (0.0743 mmol) The same operation was performed to obtain the title compound.
Yield 3.6 mg (0.00490 mmol) Yield 6.6%
MS (ESI, m / z) 507 (MH +)
H-NMR (DMSO-d6) δ 1.18-1.31 (2H, m), 1.59-1.81 (3H, m), 2.41 (2H, d), 2.55-2.87 (4H, m), 3.10-3.22 (2H, m), 3.51-3.68 (1H, m), 3.86 (2H, d), 6.87-6.96 (4H, m), 7.03 (1H, dd), 7.17 (1H, d), 7.28-7.51 (4H, m) 7.58-7.65 (2H, m), 8.04 (1H, d), 8.18 (1H, br), 8.47 (1H, br), 9.05 (2H, br), 9.21 (2H, br)
Example 165
3-[(2S) -2- (Benzenesulfonylamino) -3- [4-[(1-acetimidoyl-4-piperidyl) methyl] phenyl] propoxy] benzamidine Synthesis of ditrifluoroacetate 3-[( 2S) -2- (Benzenesulfonylamino) -3- [4- (4-piperidylmethyl) phenyl] propoxy] benzamidine The same procedure as in Example 158 was performed using 6.8 mmol (0.0094 mmol) of ditrifluoroacetate. The title compound was obtained.
Yield 1.7 mg (0.00219 mmol) Yield 23.4%
MS (ESI, m / z) 548 (MH +)
H-NMR (DMSO-d6) δ 1.10-1.28 (2H, m), 1.60-1.73 (2H, m), 1.77-1.91 (1H, m), 2.22 (3H, s), 144 (2H, d ), 2.63 (1H, dd), 2.84 (1H, dd), 3.01-3.28 (2H, m), 3.58-3.67 (1H, m), 3.82-4.01 (2H, m), 3.92 (2H, d), 6.98 (2H, d), 6.99 (2H, d), 7.11 (1H, dd), 7.21 (1H, d), 7.35-7.56 (4H, m), 7.61-7.71 (2H, m), 8.09 (1H, d), 8.45 (1H, br), 9.00 (2H, br), 9.27 (2H, br)
Example 166
(2E) -3- [4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] acrylic acid Synthesis of fluoroacetates
(2E) -3- [4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] ethyl acrylate Synthesis of trifluoroacetate
Process 1
Synthesis of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (4-iodobenzenesulfonylamino) propoxy] benzonitrile 3-[(2S ) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propoxy] benzonitrile (2.54 g, 4.34 mmol) was converted into 4N chloride. 25 ml of hydrogen in dioxane and 12.5 ml of dioxane were added. After stirring at room temperature for 24 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 40 ml of DMF. 1.77 ml (13.0 mmol) of diisopropylethylamine and 1.97 g (6.51 mmol) of 4-iodobenzenesulfonyl chloride were added at 0 ° C. After 30 minutes, the mixture was returned to room temperature and stirred for 19 hours. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 2.50 g (3.39 mmol) Yield 78%
H-NMR (CDCl3) δ 1.62-1.83 (2H, m), 1.63-2.00 (2H, m), 2.62-2.80 (1H, m), 2.83-3.00 (1H, m), 3.40-3.53 (2H, m), 3.62-3.80 (3H, m), 3.81-4.00 (2H, m), 4.40-4.45 (1H, m), 4.40-4.45 (1H, m), 5.14 (2H, s), 5.20-5.36 1H, m), 6.73 (2H, d), 6.90 (2H, d), 7.01 (2H, d), 7.24-7.44 (9H, m), 7.70 (2H, d)
Process 2
(2E) -3- [4-[(2S) -1- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (3-cyanophenoxy) -2-propylsulfa Synthesis of [Moyl] phenyl] ethyl acrylate
3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (4-iodobenzenesulfonylamino) propoxy] benzonitrile (738 mg, 1.00 mmol) was added. Dissolved in 5 ml of acetonitrile, 0.22 ml (2.0 mmol) of ethyl acrylate, 11 mg (0.05 mmol) of palladium acetate, 91 mg (0.3 mmol) of tris-o-tolylphosphine, 0.48 ml (2.0 mmol) of tributylamine And heated to reflux for 15 hours. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using dichloromethane as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 544 mg (0.75 mmol) Yield 75%
H-NMR (CDCl3) δ 0.93 (3H, s), 1.64-1.83 (2H, m), 1.85-2.00 (2H, m) 2.70-3.00 (2H, m), 3.40-3.52 (1H, m), 3.66-3.80 (3H, m), 3.82-4.28 (2H, q), 4.36-4.44 (1H, m), 5.14 (2H, s), 6.50 (1H, d), 6.72 (2H, d), 6.92 ( 2H, d), 7.28-7.40 (7H, m), 7.52 (2H, d), 6.99-7.04 (2H, m), 7.73 (2H, d)
Process 3
(2E) -3- [4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] acrylic acid Synthesis of fluoroacetates
(2E) -3- [4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] ethyl acrylate Synthesis of trifluoroacetate
(2E) -3- [4-[(2S) -1- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (3-cyanophenoxy) -2-propylsulfa Moyl] phenyl] ethyl acrylate was dissolved in 4.5 ml of 4N hydrogen chloride in dioxane, and 0.5 ml of ethanol containing 30% hydrogen chloride (W / V) was added. After stirring at room temperature for 96 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 24 ml of an ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 24 hours. The residue obtained by distilling off the solvent was added 18 ml of acetic acid containing 20% hydrogen bromide at 0 ° C. and stirred for 1 hour, then returned to room temperature and stirred for 7 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
(2E) -3- [4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] acrylic acid Fluoroacetate:
Yield 88 mg (0.11 mmol) Yield 14%
MS (ESI, m / z) 579 (MH +)
H-NMR (DMSO-d6)) δ 1.70-1.85 (2H, m), 1.98-2.12 (2H, m), 2.55-2.65 (1H, m), 2.78-2.88 (1H, m), 3.00-3.16 (2H, m), 3.18-3.30 (2H, m), 3.57-3.70 (1H, m), 3.95-4.00 (2H, m), 4.53 (1H, m), 6.60 (1H, d), 6.72 (2H , d), 6.99 (2H, d), 7.15 (1H, dd), 7.29 (1H, d), 7.39 (1H, d), 7.54 (1H, t), 7.57 (2H, d), 7.59 (1H, d), 7.67 (2H, d), 8.18 (1H, d), 8.60 (2H, br), 9.20 (2H, br), 9.38 (2H, br)
2E) -3- [4-[(2S) -1- [4- (4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] ethyl acrylate Nitri Fluoroacetate:
Yield 149 mg (0.18 mmol) Yield 23%
MS (ESI, m / z) 607 (MH +)
H-NMR (DMSO-d6)) δ 1.70-1.85 (2H, m), 1.98-2.12 (2H, m), 2.55-2.65 (1H, m), 2.78-2.88 (1H, m), 3.00-3.16 (2H, m), 3.18-3.30 (2H, m), 3.57-3.70 (1H, m), 3.95-4.00 (2H, m), 4.53 (1H, m), 6.60 (1H, d), 6.72 (2H , d), 6.99 (2H, d), 7.15 (1H, dd), 7.29 (1H, d), 7.39 (1H, d), 7.54 (1H, t), 7.57 (2H, d), 7.59 (1H, d), 7.67 (2H, d), 8.18 (1H, d), 8.60 (2H, br), 9.20 (2H, br), 9.38 (2H, br)
Example 167
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid Synthesis of ditrifluoroacetate
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] methyl benzoate Synthesis of ditrifluoroacetate
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] ethyl benzoate Synthesis of ditrifluoroacetate
Process 1
Synthesis of methyl 4-[(2S) -1- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (3-cyanophenoxy) -2-propylsulfamoyl] benzoate 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (4-iodobenzenesulfonylamino) propoxy] benzonitrile (738 mg, 1.00 mmol) was added. Dissolve in 5 ml of dimethylformamide, add 11 mg (0.05 mmol) of palladium acetate, 0.81 ml (2.0 mmol) of methanol and 0.28 ml (2.0 mmol) of triethylamine and heat at 70 ° C. for 3.5 hours in the presence of carbon monoxide. did. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 518 mg (0.76 mmol) Yield 76%
Process 2
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid Synthesis of ditrifluoroacetate
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] methyl benzoate Synthesis of ditrifluoroacetate
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] ethyl benzoate Synthesis of ditrifluoroacetate
518 mg of methyl 4-[(2S) -1- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (3-cyanophenoxy) -2-propylsulfamoyl] benzoate ( 0.76 mmol) was used as a starting material and converted according to the same procedure as in Step 5 of Example 95, followed by deprotection to obtain the title compound.
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid ditrifluoroacetate:
Yield 17 mg (0.02 mmol) Yield 3%
MS (FAB, m / z) 553 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 2.53-2.66 (1H, m), 2.80-2.90 (1H, m), 3.00-3.16 ( 2H, m), 3.20-3.30 (2H, m), 3.60-3.72 (1H, m), 3.98-4.03 (2H, m), 4.53 (1H, m), 6.72 (2H, d), 6.99 (2H, d), 7.18 (1H, dd), 7.29 (1H, d), 7.39 (1H, d), 7.50 (1H, t), 7.65 (2H, d), 7.89 (2H, d), 8.28 (1H, d ), 8.50 (2H, br), 9.05 (2H, br), 9.28 (2H, br)
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] methyl benzoate ditrifluoroacetate:
Yield 80 mg (0.10 mmol) Yield 13%
MS (FAB, m / z) 567 (MH +)
H-NMR (DMSO-d6) δ 1.35 (3H, t), 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 2.55-2.68 (1H, m), 2.80-2.90 (1H, m), 3.00-3.16 (2H, m), 3.20-3.28 (2H, m), 3.60-3.72 (1H, m), 3.96-4.00 (2H, m), 4.34 (2H, q), 4.53 (1H, m), 6.75 (2H, d), 7.02 (2H, d), 7.15 (1H, dd), 7.20 (1H, d), 7.37 (1H, d), 7.48 (1H, t), 7.69 (2H, d ), 7.91 (2H, d), 8.30 (1H, d), 8.53 (2H, br), 9.15 (2H, br), 9.26 (2H, br)
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] ethyl benzoate ditrifluoroacetate:
Yield 51 mg (0.06 mmol) Yield 8%
MS (FAB, m / z) 581 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.85 (2H, m), 2.00-2.15 (2H, m), 2.53-2.66 (1H, m), 2.80-2.90 (1H, m), 3.00-3.16 ( 2H, m), 3.20-3.30 (2H, m), 3.60-3.72 (1H, m), 3.98-4.03 (2H, m), 4.53 (1H, m), 6.72 (2H, d), 6.99 (2H, d), 7.18 (1H, dd), 7.29 (1H, d), 7.39 (1H, d), 7.50 (1H, t), 7.65 (2H, d), 7.89 (2H, d), 8.28 (1H, d ), 8.50 (2H, br), 9.05 (2H, br), 9.28 (2H, br)
Example 168
4-[(2S) -1- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid ditrifluoroacetate Synthesis of
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid ditrifluoroacetate 8 mg (0.01 mmol) Was dissolved in 2 ml of ethanol, 9 mg (0.07 mmol) of ethylacetoimidate hydrochloride and 0.5 ml of triethylamine were added, and the mixture was stirred for 24 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 3 mg (0.0037 mmol) Yield 36%
MS (ESI, m / z) 594 (MH +)
H-NMR (DMSO-d6) δ 1.60-1.80 (2H, m), 1.97-2.10 (2H, m), 2.29 (3H, s), 2.54-2.65 (1H, m), 2.69-2.90 (1H, m), 3.43-3.60 (2H, m), 3.62-3.84 (3H, m), 3.93-4.10 (2H, m), 4.55 (1H, m), 6.72 (2H, d), 6.99 (2H, d) 7.17 (1H, dd), 7.29 (1H, d), 7.39 (1H, d), 7.50 (1H, t), 7.65 (2H, d), 7.90 (2H, d), 8.27 (1H, d), 8.54-8.60 (1H, m), 9.03 (2H, br), 9.12 (1H, br), 9.28 (2H, br)
Example 169
4-[(2S) -1- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] methyl benzoate ditrifluoroacetic acid Salt synthesis
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] methyl benzoate 40 mg (0.05 mmol) ) As a starting material, and the title compound was obtained in the same manner as in Example 168.
Yield 20 mg (0.024 mmol) Yield 48%
MS (ESI, m / z) 608 (MH +)
H-NMR (DMSO-d6) δ 1.62-1.82 (2H, m), 1.98-2.12 (2H, m), 2.30 (3H, s), 2.58-2.65 (1H, m), 2.80-2.87 (1H, m), 3.20-3.40 (2H, m), 3.42-3.80 (3H, m), 3.89 (3H, s), 3.96-4.05 (2H, m), 4.53 (1H, m), 6.78 (2H, d) , 7.02 (2H, d), 7.18 (1H, dd), 7.20 (1H, d), 7.39 (1H, d), 7.45 (1H, t), 7.70 (2H, d), 7.92 (2H, d), 8.32 (1H, d), 8.60-8.70 (1H, m), 9.16 (1H, br), 9.26 (2H, br), 9.32 (2H, br)
Example 170
4-[(2S) -1- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] ethyl benzoate ditrifluoroacetic acid Salt synthesis
4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] ethyl benzoate 26 mg (0.032 mmol) ) As a starting material, and the title compound was obtained in the same manner as in Example 168.
Yield 10 mg (0.012 mmol) Yield 37%
MS (ESI, m / z) 622 (MH +)
H-NMR (DMSO-d6) δ1.34 (3H, s), 1.55-1.70 (2H, m), 2.00-2.10 (2H, m), 2.29 (3H, s), 2.55-2.68 (1H, m) , 2.77-2.88 (1H, m), 3.45-3.60 (2H, m), 3.66-3.80 (3H, m), 3.95-4.00 (2H, m), 4.34 (2H, q), 4.53 (1H, m) , 6.74 (2H, d), 7.01 (2H, d), 7.14 (1H, dd), 7.21 (1H, d), 7.38 (1H, d), 7.48 (1H, t), 7.69 (2H, d), 7.92 (2H, d), 8.29 (1H, d), 8.54-8.58 (1H, m), 8.99 (2H, br), 9.10 (1H, br), 9.26 (2H, br)
Example 171
(2E) -3- [4-[(2S) -1- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] Phenyl] acrylic acid Synthesis of ditrifluoroacetate
(2E) -3- [4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] acrylic acid The title compound was obtained in the same manner as in Example 168, using 39 mg (0.047 mmol) of fluoroacetate as a starting material.
Yield 20 mg (0.012 mmol) Yield 49%
MS (FAB, m / z) 620 (MH +)
H-NMR (DMSO-d6) δ 1.60-1.80 (2H, m), 1.95-2.10 (2H, m), 2.28 (3H, s), 2.54-2.65 (1H, m), 2.77-2.88 (1H, m), 3.45-3.60 (2H, m), 3.60-3.80 (3H, m), 3.91-4.03 (2H, m), 4.53 (1H, m), 6.60 (1H, d), 6.72 (2H, d) , 6.98 (2H, d), 7.15 (1H, dd), 7.29 (1H, d), 7.39 (1H, d), 7.50 (1H, t), 7.56 (2H, d), 7.63 (1H, d), 7.67 (2H, d), 8.18 (1H, d), 8.55-8.60 (1H, m), 9.07 (2H, br), 9.13 (1H, br), 9.28 (2H, br)
Example 172
(2E) -3- [4-[(2S) -1- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] Phenyl] ethyl acrylate Synthesis of ditrifluoroacetate
(2E) -3- [4-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] phenyl] ethyl acrylate The title compound was obtained in the same manner as in Example 168 using 72 mg (0.086 mmol) of trifluoroacetate as a starting material.
Yield 40 mg (0.046 mmol) Yield 53%
MS (FAB, m / z) 648 (MH +)
H-NMR (DMSO-d6) δ 1.29 (3H, t), 1.60-1.80 (2H, m), 1.96-2.10 (2H, m), 2.28 (3H, s), 2.54-2.65 (1H, m) 2.78-2.88 (1H, m), 3.45-3.56 (2H, m), 3.60-3.80 (3H, m), 3.95-4.02 (2H, m), 4.22 (2H, q), 4.53 (1H, m) , 6.68 (1H, d), 6.72 (2H, d), 6.98 (2H, d), 7.17 (1H, dd), 7.27 (1H, d), 7.38 (1H, d), 7.50 (1H, t), 7.56 (2H, d), 7.64 (1H, d), 7.67 (2H, d), 8.18 (1H, d), 8.50-8.60 (1H, m), 9.03 (2H, br), 9.10 (1H, br) , 9.27 (2H, br)
Example 173
2-[(2S) -1- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid ditrifluoroacetate Synthesis of
Process 1
Synthesis of benzyl 2-[(2S) -1- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (3-cyanophenoxy) -2-propylsulfamoyl] benzoate To 500 mg (0.854 mmol) of 3-[(2S) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (4-iodobenzenesulfonylamino) propoxy] benzonitrile 5 ml of 4N hydrogen chloride in dioxane and 2.5 ml of dioxane were added. After stirring at room temperature for 24 hours, the residue obtained by distilling off the solvent under reduced pressure was dissolved in 8 ml of DMF, 0.49 ml (2.56 mmol) of diisopropylethylamine, 398 mg (1.28 mmol) of 2- (benzyloxycarbonyl) benzenesulfonyl chloride. Was added at 0 ° C. After stirring for 1 hour, the mixture was returned to room temperature and further stirred for 24 hours. The reaction mixture was extracted with ethyl acetate, washed with water, 1N hydrogen chloride and saturated brine, and dried over powdered magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 490 mg (0.646 mmol) Yield 77%
H-NMR (CDCl3) δ 1.63-1.80 (2H, m), 1.82-2.00 (2H, m), 2.70-3.00 (2H, m), 3.38-3.49 (2H, m), 3.61-3.93 (4H, m), 4.22-4.45 (2H, m), 5.15 (2H, s), 5.37 (2H, m), 6.38 (1H, d), 6.55 (1H, d), 6.78 (1H, d), 6.83 (1H , t), 6.93 (1H, d), 7.00 (1H, d), 7.20-7.60 (13H, m), 7.71 (1H, d), 7.82 (1H, d)
Process 2
2-[(2S) -1- [4- (4-Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid Synthesis of ditrifluoroacetate
2-[(2S) -1- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (3-cyanophenoxy) -2-propylsulfamoyl] benzyl benzoate 490 mg ( 0.646 mmol) was used as a starting material, and conversion was carried out in the same manner as in Step 5 of Example 95, followed by deprotection to give the title compound.
Yield 50 mg (0.046 mmol) Yield 10%
MS (FAB, m / z) 552 (M +)
H-NMR (DMSO-d6) δ 1.70-1.85 (2H, m), 2.00-2.12 (2H, m), 2.60-2.62 (1H, m), 2.77-2.88 (1H, m), 3.01-3.16 ( 2H, m), 3.19-3.27 (2H, m), 3.78-3.94 (2H, m), 4.46-4.59 (2H, m), 6.77 (2H, d), 7.02 (2H, d), 7.09 (2H, d), 7.22 (1H, d), 7.31 (1H, d), 7.38 (1H, t), 7.49 (1H, dd), 7.58 (1H, d), 7.73 (1H, br), 7.80 (1H, d ), 8.15 (1H, br), 8.42-8.58 (1H, m), 9.07 (1H, br), 9.27 (1H, br)
Process 3
2-[(2S) -1- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid ditrifluoroacetate Synthesis of
2- [N-[(1S) -1-[(3-amidino-1-phenyl) oxy] methyl-2- [4- (4-piperidyl) oxy] phenyl] ethyl] sulfamoylbenzoic acid ditrifluoroacetate The title compound was obtained in the same manner as in Example 168, using 50 mg (0.046 mmol) as a starting material.
Yield 25 mg (0.030 mmol) Yield 66%
MS (FAB, m / z) 593 (M +)
H-NMR (DMSO-d6) δ 1.65-1.80 (2H, m), 1.95-2.10 (2H, m), 2.28 (3H, s), 2.59-2.70 (1H, m), 2.73-2.88 (1H, m), 3.44-3.58 (2H, m), 3.67-3.80 (2H, m), 3.82-3.94 (3H, m), 4.62 (1H, m), 6.77 (2H, d), 7.00 (2H, d) 7.10 (1H, dd), 7.21 (1H, d), 7.37 (1H, t), 7.42 (1H, d), 7.49 (1H, d), 7.58 (1H, d), 7.73 (1H, br), 7.75 (1H, d), 8.15 (1H, d), 8.57 (1H, br), 9.03 (2H, br), 9.12 (1H, br), 9.26 (2H, br)
Example 174
3-[(3R) -3- (Benzenesulfonylamino) -4- [4- (4-piperidyloxy) phenyl] butyl] benzamidine Synthesis of ditrifluoroacetate
Process 1
Synthesis of 3-[(3S) -4- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (t-butoxycarbonylamino) -1-butenyl] benzonitrile (2S ) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) methyl propionate 3.87 g (7.70 mmol) was dissolved in 77 ml of toluene. At −78 ° C., 19.3 ml (19.3 mmol) of a 1.0 M hexane solution of diisobutylaluminum hydride was added and stirred for 10 minutes. To this was added 10 ml of methanol and 20 ml of a saturated aqueous solution of potassium sodium tartrate, and the mixture was further stirred at room temperature for 1 hour. The reaction mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain an oily residue. The oily residue thus obtained was dissolved in a mixed solvent of 30 ml of ethanol and 30 ml of tetrahydrofuran, and 3.53 g (7.70 mmol) of (3-cyanobenzyl) triphenylphosphonium bromide was added at 1.15 ml (7.70 mmol) of DBU at room temperature. The mixture was further stirred for 1 hour. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain the title compound as a mixture of geometric isomers (E: Z = 2: 3).
Yield 2.33 g (4.00 mmol) Yield 52%
MS (ESI, m / z) 604 (MNa +)
H-NMR (CDCl3) δ 1.43 (9H, s), 1.69-1.83 (2H, m), 1.85-1.98 (2H, m), 2.68 (1H, dd), 2.89 (1H, dd), 3.46 (2H , dddd), 3.76 (2H, ddd), 4.42-4.50 (1H, m), 4.52-4.67 (1H, m), 5.14 (2H, s), 5.5g (1H, dd, for Z isomer), 6.20 ( 1H, dd, for E isomer), 6.41 (1H, d, for E isomer), 6.42 (1H, d, for Z isomer), 6.81 (1H, d, for Z isomer), 6.85 (1H, d, for E isomer), 7.03 (1H, d, for Z isomer), 7.11 (1H, d, for E isomer), 7.28-7.50 (9H, m)
Process 2
Synthesis of 3-[(3S) -4- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (benzenesulfonylamino) -1-butenyl] benzonitrile
2.33 g of 3-[(3S) -4- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (t-butoxycarbonylamino) -1-butenyl] benzonitrile ( 4.00 mmol) was dissolved in 20 ml of 4N hydrogen chloride dioxane solution and 10 ml of dioxane and stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure to obtain an oily residue. The oily residue thus obtained was dissolved in 20 ml of DMF, and 2.09 ml (12.00 mmol) of diisopropylethylamine and 1.06 g (6.00 mmol) of benzenesulfonyl chloride were added at 0 ° C. and stirred for 2.5 hours. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound as a mixture of geometric isomers (E: Z = 2: 3).
Yield 2.11 g (3.39 mmol) Yield 85%
H-NMR (CDCl3) δ 1.70-1.83 (2H, m), 1.86-2.01 (2H, m), 2.73 (1H, dd, for Z isomer), 2.81 (1H, d, for E isomer), 2.86 ( 1H, dd, for Z isomer), 2.98 (1H, d, for E isomer), 3.45 (2H, ddd), 3.76 (2H, ddd), 4.11-4.22 (1H, m), 4.43-4.49 (1H, m ), 5.14 (2H, s), 5.52 (1H, dd, for Z isomer), 5.94 (1H, dd, for E isomer), 6.27 (1H, d, for E isomer), 6.34 (1H, d, for Z isomer), 6.77 (2H, d), 6.90 (2H, d), 7.08 (1H, d), 7.26-7.38 (9H, m), 7.49 (1H, t), 7.56 (1H, d)
Process 3
3-[(3R) -3- (Benzenesulfonylamino) -4- [4- (4-piperidyloxy) phenyl] butyl] benzamidine Synthesis of ditrifluoroacetate
669 mg (1.08 mmol) of 3-[(3S) -4- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (benzenesulfonylamino) -1-butenyl] benzonitrile, 20 mg of 10% palladium carbon was dissolved in a mixed solvent of 2 ml of methanol and 3 ml of dichloromethane, and stirred at room temperature for 2 hours under a hydrogen atmosphere of 1 atm. Palladium on carbon was removed by suction filtration, and the filtrate was concentrated to give an oily residue. The oily residue thus obtained was added to 10 ml of ethanol containing 30% hydrogen chloride (W / V) and stirred overnight at room temperature. The residue obtained by distilling off the solvent was dissolved in 30 ml of an ethanol solution containing 10% ammonia (w / v) at room temperature and stirred overnight at room temperature. The residue obtained by distilling off the solvent was dissolved in 20 ml of an acetic acid solution of hydrogen bromide and stirred at room temperature for 2 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 0.302 g (0.41 mmol) Yield 38%
H-NMR (DMSO-d6) δ 1.50-1.70 (2H, m), 1.70-1.86 (2H, m), 2.00-2.11 (2H, m), 2.33-2.74 (4H, m), 3.01-3.16 ( 2H, m), 3.18-3.30 (2H, m), 3.31-3.44 (1H, m), 4.51-4.60 (1H, m), 6.81 (2H, d), 6.96 (2H, d), 7.33 (1H, d), 7.43-7.62 (5H, m), 7.74 (2H, d), 7.80 (1H, d), 8.53 (2H, br), 9.08 (2H, s), 9.22 (2H, s)
Example 175
3-[(3R) -3- (Benzenesulfonylamino) -4- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] butyl] benzamidine Synthesis of ditrifluoroacetic acid
3-[(3R) -3- (benzenesulfonylamino) -4- [4- (4-piperidyloxy) phenyl] butyl] benzamidine 10.7 mg (0.015 mmol) of ditrifluoroacetate was used as a starting material. The title compound was obtained in the same manner as in Example 158.
Yield 11.1 mg (0.014 mmol) Yield 95%
MS (ESI, m / z) 548 (MH +)
H-NMR (DMSO-d6) δ 1.50-1.82 (4H, m), 1.97-2.10 (2H, m), 2.29 (3H, s), 2.34-2.72 (4H, m), 3.22-3.59 (4H, m), 3.68-3.82 (1H, m), 4.57-4.66 (1H, m), 6.82 (2H, d), 6,97 (2H, d), 7.33 (1H, d), 7.43-7.62 (5H, m), 7.74 (2H, d), 7.81 (1H, d), 8.60 (1H, s), 9.15 (1H, s), 9.20 (2H, s), 9.23 (2H, s)
Example 176
Synthesis of 3-[(3S, 1Z) -3- (benzenesulfonylamino) -4- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -1-butenyl] benzamidine ditrifluoroacetate
3-[(3S) -4- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -3- (benzenesulfonylamino) -1-butenyl] benzonitrile (120 mg, 0.19 mmol) was added. The mixture was added to 2 ml of ethanol containing 30% hydrogen chloride (W / V) and stirred overnight at room temperature. Subsequently, the mixture was dissolved in 5 ml of an ethanol solution containing 10% ammonia (w / v) at room temperature and stirred overnight at room temperature. The residue obtained by distilling off the solvent was dissolved in 5 ml of an acetic acid solution of hydrogen bromide under ice cooling and stirred for 2 hours. The residue obtained by distilling off the solvent was converted in the same manner as in Example 158 to obtain the title compound.
Yield 12 mg (0.016 mmol) Yield 8.4%
MS (ESI, m / z) 546 (MH +)
H-NMR (DMSO-d6) δ 1.64-1.81 (2H, m), 1.96-2.10 (2H, m), 2.28 (3H, s), 2.46-2.52 (1H, m), 2.67-2.73 (1H, m), 3.47-3.52 (2H, m), 3.70-3.77 (2H, m), 4.11-4.23 (1H, m), 4.56-4.67 (m, 1H), 5.47 (1H, dd), 6.27 (1H, d), 6.82 (2H, d), 6.96 (2H, d), 7.06 (1H, d), 7.28 (1H, s), 7.42-7.49 (3H, m), 7.54-7.58 (3H, m), 7.65 (1H, d), 8.02 (1H, d), 8.58 (1H, s), 9.12 (1H, s), 9.18 (2H, s), 9.29 (2H, s)
Example 177
(2S) -N- (3-Amidinophenyl) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propionamide Synthesis of ditrifluoroacetate
Process 1
Synthesis of methyl (2S) -2- (benzenesulfonylamino) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propionate
(2S) -3- [4- [1- (Benzyloxycarbonyl) -4-piperidyloxy] phenyl] -2- (t-butoxycarbonylamino) propionate 3.96 g (7.94 mmol) was converted into 4N chloride. It melt | dissolved in 30 ml of hydrogen dioxane solutions, and stirred at room temperature for 4 hours. The oily residue obtained by distilling off the solvent was dissolved in 40 ml of DMF, 5.14 ml (23.83 mmol) of diisopropylethylamine and 2.10 g (11.91 mmol) of benzenesulfonium chloride were added at 0 ° C. and 2.5 ml at room temperature. Stir for hours. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 3.5 g (6.52 mmol) Yield 82%
H-NMR (CDCl3) δ1.60-2.00 (4H, m), 2.95 (1H, d), 3.45 (2H, ddd), 3.47 (3H, s), 3.76 (2H, ddd), 4.19 (1H, dt ), 4.41-4.49 (1H, m), 5.16 (2H, s), 6.78 (2H, d), 6.98 (2H, d), 7.30-7.58 (8H, m), 7.76 (2H, d)
Process 2
Synthesis of (2S) -N- (3-amidinophenyl) -2- (benzenesulfonylamino) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propionamide (2S)- 2.75 g (3.26 mmol) of methyl 2- (benzenesulfonylamino) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propionate in a mixed solvent of 10 ml of methanol and 10 ml of tetrahydrofuran After dissolution, 6.52 ml (6.52 mmol) of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. overnight. After washing with ether, the mixture was acidified with concentrated hydrochloric acid, and dichloromethane was used as an extraction solvent, and an oily residue was obtained by the same isolation procedure as in Step 1 of Example 1. The oily residue thus obtained was dissolved in 60 ml of pyridine, 747 mg (3.61 mmol) of 3-aminobenzamidine dihydrochloride and 750 mg (3.92 mmol) of WSC were added, and the mixture was stirred overnight at room temperature. The residue obtained by distilling off the solvent was purified by silica gel column chromatography to obtain the title compound.
Yield 1.89 g (2.90 mmol) Yield 89%
H-NMR (CDCl3) δ1.72-1.83 (2H, m), 1.85-2.00 (2H, m), 3.32 (1H, dd), 3.44 (2H, ddd), 3.61 (1H, dd), 3.78 (2H , ddd), 4.04-4.14 (1H, m), 4.42-4.51 (1H, m), 5.32 (2H, s), 6.84 (2H, d), 7.18 (2H, d), 7.28-7.38 (9H, m ), 7.43-7.50 (2H, m), 7.64-7.69 (2H, m), 7.77-7.83 (1H, m), 8.02 (4H, s)
Process 3
(2S) -N- (3-Amidinophenyl) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propionamide Synthesis of ditrifluoroacetate
(2S) -N- (3-Amidinophenyl) -2- (benzenesulfonylamino) -3- [4- [1- (benzyloxycarbonyl) -4-piperidyloxy] phenyl] propionamide 90 mg (0.13 mmol) Was dissolved in 20 ml of hydrogen bromide in acetic acid and stirred at room temperature for 2 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction. Yield 34 mg (0.065 mmol) Yield 49%
MS (ESI, m / z) 522 (MH +)
H-NMR (DMSO-d6) δ 1.71-1.88 (2H, m), 2.02-2.16 (2H, m), 2.68 (1H, dd), 2.88 (1H, dd), 3.03-3.17 (2H, m) , 3.20-3.30 (2H, m), 4.05-4.15 (1H, m), 4.54-4.62 (1H, m), 6.83 (2H, d), 7.10 (2H, d), 7.34 (2H, dt), 7.42 -7.50 (2H, m), 7.57 (2H, d), 7.70 (1H, d), 7.92 (1H, d), 8.38 (1H, d), 8.58 (2H, br), 9.13 (2H, s), 9.31 (2H, s), 10.42 (1H, s)
Example 178
(2S) -N- (3-amidinophenyl) -2- (benzenesulfonylamino) -3- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] propionamide Synthesis of ditrifluoroacetate
Starting from (2S) -N- (3-amidinophenyl) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propionamide ditrifluoroacetate 80 mg (0.153 mmol) The title compound was obtained in the same manner as in Example 158.
Yield 30 mg (0.038 mmol) Yield 25%
MS (ESI, m / z) 563 (MH +)
H-NMR (DMSO-d6) δ 1.65-1.72 (2H, m), 1.98-2.12 (2H, m), 2.30 (3H, s), 2.67 (1H, dd), 2.88 (1H, dd), 3.46 -3.60 (2H, m), 3.69-3.82 (2H, m), 4.04-4.16 (1H, m), 4.58-4.68 (1H, m), 6.82 (2H, d), 7.11 (2H, d), 7.33 (2H, t), 7.42-7.48 (2H, m), 7.53 (2H, t), 7.70 (1H, d), 7.92 (1H, s), 8.38 (1H, d), 8.60 (1H, s), 9.11 (2H, s), 9.12 (1H, s), 9.32 (2H, s), 10.41 (1H, s)
Example 179
Synthesis of 3-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] -4-iodobenzamidine ditrifluoroacetate
Process 1
Synthesis of 3-[(2S) -3- [4- (1-benzyloxycarbonyl-4-piperidyloxy) phenyl] -2- (t-butoxycarbonylamino) propoxy] -4-iodobenzonitrile 4- [4 -[(2S) -3-Chloro-2- (t-butoxycarbonylamino) propyl] phenoxy] piperidine-1-carboxylate 1.3 g (2.6 mmol), 3-hydroxy-4-iodobenzonitrile 686 mg (2 0.8 mmol) and 390 mg (2.8 mmol) of potassium carbonate were dissolved in dimethylformamide and stirred at 65 ° C. for 4 days. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent. This was used in the next reaction without purification.
Process 2
Synthesis of 3-[(2S) -2- (benzenesulfonylamino) -3- [4- (1-benzyloxycarbonyl-4-piperidyloxy) phenyl] propoxy] -4-iodobenzonitrile 3-[(2S) -3- [4- (1-Benzyloxycarbonyl-4-piperidyloxy) phenyl] -2- (t-butoxycarbonylamino) propoxy] -4-iodobenzonitrile (1.6 g, 2.7 mmol) was converted into 4N chloride. Dissolved in hydrogen in dioxane and stirred at room temperature overnight. The solvent was distilled off, and the residue was dissolved in dimethylformamide. Under ice cooling, 1 ml (6 mmol) of N, N-diisobutylethylamine and 0.34 ml (2.7 mmol) of benzenesulfonyl chloride were added and stirred for 2 hours. A crude product was obtained by the same isolation operation as in Step 1 of Example 1 using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 1.17 g (1.56 mmol) Yield 71%
H-NMR (CDCl3) δ 1.70-1.80 (2H, m), 1.85-1.95 (2H, m), 2.85-3.05 (2H, m), 3.40-3.50 (2H, m), 3.70-3.90 (5H, m), 4.40 (1H, m), 4.90 (1H, d), 5.15 (2H, s), 6.71 (1H, s), 6.75 (2H, d), 6.95 (2H, d), 7.01 (1H, d ), 7.30-7.55 (8H, m), 7.76-7.81 (2H, m), 7.89 (1H, d)
Process 3
Synthesis of 3-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] -4-iodobenzamidine ditrifluoroacetate
3-[(2S) -2- (benzenesulfonylamino) -3- [4- (1-benzyloxycarbonyl-4-piperidyloxy) phenyl] propoxy] -4-iodobenzonitrile (97 mg, 0.13 mmol) The product was dissolved in 3 ml of normal hydrogen chloride in dioxane, 0.5 ml of ethanol was added, and the mixture was stirred at room temperature for 4 days. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 30 ml of an ethanol solution containing 10% ammonia (w / v) and stirred overnight at room temperature. The solvent was distilled off, and the resulting residue was dissolved in acetic acid containing 20% hydrogen bromide under ice cooling and stirred for 2 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 35 mg (0.04 mmol) Yield 31%
MS (ESI, m / z) 635 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.85 (2H, m), 2.00-2.12 (2H, m), 2.50-3.60 (7H, m), 4.05 (2H, m), 4.50 (1H, m) , 6.74 (2H, d), 6.98 (2H, d), 7.21 (1H, d), 7.26 (1H, s), 7.37-7.67 (5H, m), 8.30 (1H, d), 8.16 (1H, d ), 8.56 (2H, brs), 9.18 (2H, brs), 9.32 (2H, brs)
Example 180
3- [4-Amidino-2-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] phenyl] -2-oxopropionic acid ditrifluoroacetate Synthesis of
Process 1
Synthesis of methyl 2-acetylamino-3- [2-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] -4-cyanophenyl] acrylate
3-[(2S) -2- (benzenesulfonylamino) -3- [4- (1-benzyloxycarbonyl-4-piperidyloxy) phenyl] propoxy] -4-iodobenzonitrile 197 mg (0.26 mmol), 2 -74.4 mg (0.52 mmol) of methyl acetaminoacrylate was dissolved in 6 ml of acetonitrile, 7.3 mg (0.03 mmol) of palladium (II) acetate, 55 mg (0.18 mmol) of tri-o-tolylphosphine, tributylamine 96 mg (0.52 mmol) was added and heated to reflux overnight. The solvent was distilled off and ethyl acetate was used as an extraction solvent, followed by a conventional method to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound. Yield 111 mg (0.15 mmol) Yield 58%
H-NMR (CDCl3) δ1.68-1.80 (2H, m), 1.84-1.96 (2H, m), 2.07 (3H, s), 2.75-2.90 (2H, m), 3.40-3.50 (2H, m) , 3.70-3.95 (8H, m), 4.40 (1H, m), 5.15 (2H, s), 5.35 (1H, d), 6.73 (2H, d), 6.89 (1H, s), 6.91 (2H, d ), 7.22 (1H, d), 7.28-7.47 (9H, m), 7.53 (1H, m), 7.74-7.76 (2H, m)
Process 2
3- [4-Amidino-2-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] phenyl] -2-oxopropionic acid ditrifluoroacetate Synthesis of
4 mg of methyl 2-acetylamino-3- [2-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] -4-cyanophenyl] acrylate The product was dissolved in 10 ml of normal hydrogen chloride in dioxane, 2 ml of ethanol was added, and the mixture was stirred at room temperature for 2 days. The residue obtained by distilling off the solvent was dissolved in an ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 3 days. The solvent was distilled off, and the resulting residue was dissolved in 10 ml of acetic acid containing 20% hydrogen bromide under ice cooling and stirred for 3 hours. To the residue obtained by distilling off the solvent, 25 ml of 3N hydrogen chloride and 8 ml of acetic acid were added and heated to reflux for 5 hours. The residue obtained by distilling off the solvent under reduced pressure was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 152 mg (0.19 mmol) Yield 30%
MS (ESI, m / z) 595 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.82 (2H, m), 2.00-2.12 (2H, m), 2.55 (1H, m), 2.90 (1H, m), 3.02-4.05 (7H, m) , 4.15 (1H, d, keto form), 4.30 (1H, d, keto form), 4.50 (1H, m), 6.70-7.02 (4H, m), 6.91 (1H, s, enol form), 7.15-7.70 (7H, m), 8.23 (1H, d), 8.34 (1H, d), 8.6 (2H, brs), 9.05-9.30 (4H, m)
Example 181
3- [4-Amidino-2-[(2S) -3- [4- (1-acetimidoyl-4-piperidyloxy) phenyl] -2- (benzenesulfonylamino) propoxy] phenyl] -2-oxopropion Acid Synthesis of ditrifluoroacetate
3- [4-Amidino-2-[(2S) -2- (benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] phenyl] -2-oxopropionic acid ditrifluoroacetate 162 mg (0.2 mmol) was dissolved in 5 ml of ethanol, 1.5 g (15 mmol) of triethylamine and 435 mg (3.5 mmol) of ethyl acetimidate hydrochloride were added, and the mixture was stirred at room temperature for 14 days. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 117 mg (0.135 mmol) Yield 67%
MS (ESI, m / z) 636 (MH +)
H-NMR (DMSO-d6) δ 1.60-1.80 (2H, m), 1.95-2.10 (2H, m), 2.25 (3H, s), 2.60 (1H, m), 2.90 (1H, m), 3.30 -4.10 (7H, m), 4.22 (1H, d, keto form), 4.45 (1H, d, keto form), 4.59 (1H, m), 6.70-7.00 (4H, m), 6.90 (1H, s, enol form), 7.15-7.67 (7H, m), 8.23 (1H, d), 8.33 (1H, d), 8.58 (1H, brs), 9.00-9.30 (5H, m), 9.80 (1H, br, enol form)
Example 182
Measurement of activated blood coagulation factor X inhibitory activity was carried out in the same manner as in Example 93. Representative compounds (Example numbers) and the results are shown in Table 2 below.
Example 183
The thrombin inhibitory activity was measured in the same manner as in Example 94. Representative compounds (Example numbers) and the results are shown in Table 2 below.
Example 184
Measurement of anticoagulant activity
Anticoagulant activity was determined using a prothrombin time (PT) assay. PT measurement was performed as shown below. That is, blood was collected from a healthy person, and 1/10 volume of 3.8% trisodium citrate aqueous solution was added, and plasma was separated by centrifugation. To 45 μl of plasma, 5 μl of DMSO solution containing the evaluation compound was added and incubated at room temperature for 2 minutes. The test tube containing the plasma solution was placed in a Sysmex CA-3000 fully automated blood coagulation analyzer (manufactured by Toa Electronics Co., Ltd.), incubated at 37 ° C for 3 minutes, and Sysmex PT II (manufactured by Toa Medical Electronics Co., Ltd., rabbit brain tissue). 100 μl of thromboplastin, 13.2 mM calcium chloride) was added. PT was automatically measured by the same apparatus. A control was obtained by adding DMSO (5 μl) instead of the evaluation compound solution, and a negative logarithmic value of the evaluation compound concentration that doubles the PT of the control was obtained (abbreviated as PT2) and used as an index of anticoagulant activity. The anticoagulant activity of representative compounds is shown in Table 2 below.
Figure 0004103147
However, in the table, the compound of Example 122 is N- [3- (3-amidinophenoxy) propyl] -4-amidinobenzamide ditrifluoroacetate, and the compound of Example 154 is 3-[(2S) -2. -(Benzenesulfonylamino) -3- [4- (4-piperidyloxy) phenyl] propoxy] benzamidine ditrifluoroacetate, the compound of Example 167 is 4-[(2S) -1- [4- (4 -Piperidyloxy) phenyl] -3- (3-amidinophenoxy) -2-propylsulfamoyl] benzoic acid ditrifluoroacetate, respectively.
From this result, it can be seen that the benzamidine derivative of the present invention has a high inhibitory activity specific to activated blood coagulation factor X and exhibits a high anticoagulant action based on this.
The structural formulas of the compounds of the present invention described in Examples 95 to 181 are shown below.
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Example 185
2-Acetamido-3- [4-amidino-2-[(2R) -2- (4-amidinobenzoylamino) -3-ethoxycarbonylpropoxy] phenyl] acrylate methyl ditrifluoroacetate synthesis
Process 1
Synthesis of benzyl (3R) -3-t-butoxycarbonylamino-4-hydroxybutanoate
Nt-butoxycarbonyl-D-aspartic acid-β-benzyl ester (15.0 g, 46.4 mmol) and triethylamine (6.47 ml, 46.4 mmol) were dissolved in tetrahydrofuran (230 ml), and ice-cooled ethyl chloroformate (4.4 ml) was dissolved. (46.4 mmol) was added and stirred for 15 minutes. The resulting precipitate was removed by suction filtration, and 5 g of ice and 1.8 g (46.4 mmol) of sodium borohydride were added to the filtrate under ice cooling and stirred for 1.5 hours. Subsequently, 200 ml of 1N aqueous hydrogen chloride solution was added thereto, and the mixture was further stirred at room temperature for 1 hour. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography (hexane: ethyl acetate = 2: 1, v / v) gave the title compound.
Yield 10.2 g (32.8 mmol) Yield 71%
1H-NMR (CDCl3) δ: 1.42 (9H, s), 2.66 (2H, d), 3.65 (2H, dd), 4.00 (1H, ddt), 5.14 (2H, s), 7.35-7.40 (5H, m )
Process 2
Synthesis of 3-hydroxy-4-iodobenzonitrile
To a solution of 22.3 g (89.7 mmol) of 3-hydroxy-4-iodobenzoic acid in 300 ml of tetrahydrofuran, 19.7 ml (206 mmol) of ethyl chloroformate and 28.7 ml (206 mmol) of triethylamine were added at 0 ° C. After stirring for 15 minutes, the produced triethylamine hydrochloride was filtered off, and the filtrate was added at 0 ° C. to 300 ml of a tetrahydrofuran solution obtained by bubbling ammonia. After stirring at room temperature for 10 hours, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in 450 ml of dioxane, and 17.4 ml (117 mmol) of trifluoromethanesulfonic anhydride and 21.8 ml (269 mmol) of pyridine were added at 0 ° C. . After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the resulting residue was treated according to a conventional method using chloroform as an extraction solvent to obtain an oily residue. To a solution of the obtained residue in 180 ml of tetrahydrofuran: methanol (1: 1), 1N aqueous sodium hydroxide solution (90 ml, 90.0 mmol) was added at room temperature. After stirring for 4 hours, the solvent was distilled off under reduced pressure, and the resulting residue was washed with dichloromethane. Subsequently, the mixture was acidified with 1N hydrogen chloride and treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography yielded the title compound.
Yield 9.29 g (37.9 mmol) Yield 42%
MS (FAB, m / z) 246 (MH +)
1H-NMR (CDCl3) δ: 5.63 (1H, br), 6.96 (1H, dd), 7.23 (1H, d), 7.79 (1H, d)
Process 3
Synthesis of benzyl (3R) -3-t-butoxycarbonylamino-4- (5-cyano-2-iodophenoxy) butanoate
10.16 g (32.8 mmol) of benzyl (3R) -3-tert-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of toluene, and 10.5 g (42.7 mmol) of 3-hydroxy-4-iodobenzonitrile was dissolved. 11.2 g (42.7 mmol) of triphenylphosphine and 7.4 g (42.7 mmol) of N, N, N ′, N′-tetramethylazodicarboxamide were added under ice-cooling, and the mixture was stirred overnight at room temperature. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, v / v) to obtain the title compound.
Yield 11.9 g (22.1 mmol) Yield 67%
1H-NMR (CDCl3) δ: 1.47 (9H, s), 2.90 (2H, t), 4.03 (1H, dd), 4.15 (1H, dd), 4.40-4.50 (1H, m), 5.19 (2H, s) ), 7.01 (1H, d), 7.30 (1H, s), 7.35-7.40 (5H, m), 7.92 (1H, d)
Process 4
Synthesis of (1R) -1-benzyloxycarbonylmethyl-2- (5-cyano-2-iodophenoxy) ethylammonium chloride
11.9 g (22.1 mmol) of benzyl (3R) -3-t-butoxycarbonylamino-4- (5-cyano-2-iodophenoxy) butanoate was dissolved in 120 ml of 4N hydrogen chloride in dioxane, and 0 ° C. For 1 hour followed by 2 hours at room temperature. To the oily residue obtained by distilling off the solvent, 50 ml of a mixed solvent of hexane and ethyl acetate (1: 1, v / v) was added, and the precipitate was collected by filtration to obtain the title compound.
Yield 6.1 g (12.9 mmol) Yield 58%
MS (ESI, M / Z) 437 (MH +)
1H-NMR (DMSO-d6) δ: 3.02 (2H, d), 3.94 (1H, ddt), 4.30 (1H, dd), 4.34 (1H, dd), 5.16 (2H, s), 7.26 (1H, dd ), 7.32-7.40 (5H, m), 7.54 (1H, s), 8.03 (1H, d), 8.52 (2H, br s)
Process 5
Synthesis of benzyl (3R) -4- (5-cyano-2-iodophenoxy) -3- (4-cyanobenzoylamino) butanoate
(1R) -1-Benzyloxycarbonylmethyl-2- (5-cyano-2-iodophenoxy) ethylammonium chloride 4.73 g (10 mmol), 4-cyanobenzoic acid 2.9 g (20 mmol), 1-hydroxybenzotriazole 3.0 g (22 mmol) and 6.1 ml (44 mmol) of triethylamine were dissolved in 50 ml of dichloromethane, and 4.2 g (22 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added under ice cooling, Stir for 10 minutes followed by 1 hour at room temperature. Water was added to stop the reaction, and a crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequently, the title compound was obtained by purification by silica gel column chromatography (hexane: ethyl acetate = 3: 1, v / v).
Yield 2.8 g (5.0 mmol) Yield 50%
1H-NMR (CDCl3) δ: 2.93 (1H, dd), 3.08 (1H, dd), 4.13 (1H, dd), 4.30 (1H, dd), 4.94 (1H, dddd), 5.14 (1H, d), 5.19 (1H, d), 6.96 (1H, d), 7.03 (1H, dd), 7.28-7.33 (5H, m), 7.72 (2H, d), 7.86 (2H, d), 7.88 (1H, d)
Step 6
Synthesis of methyl 2-acetamido-3- [2-[(2R) -3-ethoxycarbonyl-2- (4-cyanobenzoylamino) propoxy] -4-cyanophenyl] acrylate
(3R) -4- (5-cyano-2-iodophenoxy) -3- (4-cyanobenzoylamino) butanoic acid benzyl 1.28 g (2.27 mmol), methyl 2-acetamidoacrylate 975 mg (6.81 mmol) , 415 mg (1.36 mmol) of tris (2-methylphenyl) phosphine, 0.95 ml (6.81 mmol) of triethylamine and 0.5 ml of dimethylformamide were dissolved in 8.0 ml of acetonitrile, and 56 mg (0.23 mmol) of palladium acetate was dissolved at room temperature. And stirred at 90 ° C. for 12 hours. The residue obtained by removing the solvent was purified by silica gel column chromatography (chloroform: methanol = 30: 1, v / v) to obtain the title compound.
Yield 991 mg (1.71 mmol) Yield 75%
Step 7
2-Acetamido-3- [4-amidino-2-[(2R) -2- (4-amidinobenzoylamino) -3-ethoxycarbonylpropoxy] phenyl] acrylate methyl ditrifluoroacetate synthesis
2-acetamido-3- [2-[(2R) -3-ethoxycarbonyl-2- (4-cyanobenzoylamino) propoxy] -4-cyanophenyl] methyl 398 mg (0.69 mmol) was added to 1.0 ml of ethanol. Then, 10.0 ml of 4N hydrogen chloride in dioxane was added and stirred at room temperature for 21 hours. The residue obtained by distilling off the solvent was dissolved in 10.0 ml of ethanol, 1.0 g (10.4 mmol) of ammonium carbonate was added, and the mixture was stirred at room temperature for 12 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 118.6 mg (0.15 mmol) Yield 22%
MS (ESI, M / Z) 553 (MH +)
1H-NMR (DMSO-d6) δ: 1.17 (3H, t), 1.96 (3H, s), 2.81 (1H, d), 3.66 (3H, s), 4.08 (2H, q), 4.23 (1H, dd ), 4.31 (1H, dd), 4.76 (1H, br s), 7.28 (1H, s), 7.44 (1H, dd), 7.53 (1H, d), 7.73 (1H, d), 7.90 (2H, d ), 8.01 (2H, d), 8.87 (1H, d), 9.28 (2H, s), 9.32 (2H, s), 9.35 (2H, s), 9.42 (2H, s), 9.68 (2H, s)
Example 186
(3R) -3- (4-Amidinobenzoylamino) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] butanoic acid Synthesis of ditrifluoroacetate
Methyl 2-acetamido-3- [4-amidino-2-[(2R) -2- (4-amidinobenzoylamino) -3-ethoxycarbonylpropoxy] phenyl] acrylate 118.6 mg (0. 15 mmol) is dissolved in 10.0 ml of 6N hydrochloric acid and stirred at 60 ° C. for 4 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 56.8 mg (0.081 mmol) Yield 54%
MS (ESI, M / Z) 470 (MH +)
1H-NMR (DMSO-d6) δ: 2.27 (2H, t), 4.02 (1H, dd), 4.19 (1H, dd), 4.72 (1H, br s). 6.78 (1H, s), 7.35 (1H, s), 7.43 (1H, d), 7.90 (2H, d), 8.02 (2H, d), 9.10 (1H, d), 9.31 (4H, s), 9.42 (4H, s)
Example 187
Synthesis of methyl 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- (4-dimethylcarbamoylbenzoylamino) propoxy] phenyl] acrylate trifluoroacetate
Process 1
Synthesis of (3R) -4- (5-cyano-2-iodophenoxy) -3- (4-dimethylcarbamoylbenzoylamino) butanoic acid benzyl
(1R) -1-Benzyloxycarbonylmethyl-2- (5-cyano-2-iodophenoxy) ethylammonium chloride 2.05 g (4.33 mmol), 4-dimethylcarbamoylbenzoic acid 1.25 g (6.49 mmol), 994 mg (7.35 mmol) of 1-hydroxybenzotriazole and 2.71 ml (19.46 mmol) of triethylamine were dissolved in 25 ml of dichloromethane, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1. 41 g (7.35 mmol) was added and stirred for 10 minutes followed by 18 hours at room temperature. Water was added to stop the reaction, and a crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequently, the title compound was obtained by purification by silica gel column chromatography (hexane: ethyl acetate = 3: 1, v / v).
Yield 2.30 g (3.76 mmol) Yield 87%
1H-NMR (DMSO-d6) δ: 2.96 (3H, s), 2.97 (1H, dd), 3.07 (1H, dd), 3.12 (3H, s), 4.16 (1H, dd), 4.30 (1H, dd ), 4.89-4.99 (1H, m), 5.14 (1H, d), 5.20 (1H, d), 6.97 (1H, d), 7.02 (1H, dd), 7.29-7.33 (5H, m), 7.44 ( 2H, d), 7.80 (2H, d), 7.88 (1H, d)
Process 2
Synthesis of methyl 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- (4-dimethylcarbamoylbenzoylamino) propoxy] phenyl] acrylate trifluoroacetate
1.76 g (2.88 mmol) of benzyl (3R) -4- (5-cyano-2-iodophenoxy) -3- (4-dimethylcarbamoylbenzoylamino) butanoate, 1.24 g of methyl 2-acetamidoacrylate (8 .63 mmol), 536 mg (1.73 mmol) of tris (2-methylphenyl) phosphine, 1.2 ml (8.63 mmol) of triethylamine and 0.5 ml of dimethylformamide were dissolved in 10 ml of acetonitrile, and 70 mg (0.29 mmol) of palladium acetate was dissolved. It added at room temperature and stirred at 100 degreeC for 5.5 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 30: 1, v / v), then dissolved in 1.5 ml of ethanol, and 15 ml of 4N hydrogen chloride in dioxane was added. The mixture was further stirred at room temperature for 15 hours. Subsequently, the residue obtained by removing the solvent was dissolved in 20.0 ml of ethanol, 974 mg (10.13 mmol) of ammonium carbonate was added, and the mixture was stirred at room temperature for 14 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 536 mg (0.77 mmol) Yield 27%
MS (ESI, M / Z) 582 (MH +)
1H-NMR (DMSO-d6) δ: 1.08 (3H, t), 1.96 (3H, s), 2.81 (2H, d), 2.90 (3H, s), 2.99 (3H, s), 3.64 (3H, s ), 4.07 (2H, q), 4.24 (2H, t), 4.70-4.79 (1H, m), 7.30 (1H, s), 7.42 (1H, d), 7.48 (2H, d), 7.70 (1H, d), 7.84 (2H, d), 8.69 (1H, d), 9.10 (2H, s), 9.32 (2H, s), 9.67 (1H, s)
Example 188
Synthesis of (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- (4-dimethylcarbamoylbenzoylamino) butanoic acid trifluoroacetate
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- (4-dimethylcarbamoylbenzoylamino) propoxy] phenyl] acrylic acid methyl trifluoroacetate salt 151 mg (0.22 mmol) Is dissolved in 6 ml of 6N hydrochloric acid and stirred at 60 ° C. for 3 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 49.2 mg (0.08 mmol) Yield 37%
MS (ESI, M / Z) 499 (MH +)
1H-NMR (DMSO-d6) δ: 2.69 (1H, d), 2.74 (1H, d), 2.87 (3H, s), 2.98 (2H, s), 4.22 (1H, d), 4.26 (1H, d ), 4.60-4.76 (1H, m), 7.30 (1H, s), 7.40 (1H, d), 7.48 (2H, d), 7.50 (1H, s), 7.88 (2H, d), 8.32 (1H, d), 9.02 (2H, s), 9.26 (2H, s)
Example 189
Synthesis of (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- (4-carboxylbenzoylamino) butanoic acid trifluoroacetate
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- (4-dimethylcarbamoylbenzoylamino) propoxy] phenyl] methyl acrylate 54 mg (0.086 mmol) trifluoroacetate Is dissolved in 4 ml of 6N hydrochloric acid and stirred at 80 ° C. for 2 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 10.5 mg (0.02 mmol) Yield 21%
MS (ESI, M / Z) 472 (MH +)
1H-NMR (DMSO-d6) δ: 2.75 (2H, d), 4.24 (2H, d), 4.60-4.76 (1H, m), 6.79 (1H, s), 7.36 (1H, d), 7.45 (1H , d), 7.48 (1H, s), 7.90 (2H, d), 8.02 (2H, d), 8.32 (1H, d), 9.04 (2H, s), 9.25 (2H, s)
Example 190
Of 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-carbonyl) benzoylamino] propoxy] phenyl] acrylate methyl trifluoroacetate Composition
Process 1
Synthesis of benzyl (3R) -4- (5-cyano-2-iodophenoxy) -3- [4- (pyrrolidine-1-carbonyl) benzoylamino] butanoate
(1R) -1-Benzyloxycarbonylmethyl-2- (5-cyano-2-iodophenoxy) ethylammonium chloride 2.0 g (4.23 mmol), 4-pyrrolidine-1-carbonyl) benzoic acid 1.02 g (4 .65 mmol), 630 mg (4.65 mmol) of 1-hydroxybenzotriazole and 1.30 ml (9.31 mmol) of triethylamine were dissolved in 40 ml of dichloromethane, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide was cooled with ice. 890 mg (4.65 mmol) of hydrochloride was added and stirred for 10 minutes, followed by stirring at room temperature for 18 hours. Water was added to stop the reaction, and the mixture was treated according to a conventional method using dichloromethane as an extraction solvent to obtain the title compound.
Yield 2.61 g (4.09 mmol) Yield 97%
1H-NMR (CDCl3) δ: 1.83 to 2.02 (4H, m), 2.95 (1H, dd), 3.08 (1H, dd), 3.37 (2H, t), 3.64 (2H, t), 4.15 (1H, dd ), 4.31 (1H, dd), 4.89-5.00 (1H, m), 5.13 (1H, d), 5.20 (1H, d), 6.97 (1H, d), 7.02 (1H, dd), 7.29-7.33 ( 5H, m), 7.54 (2H, d), 7.79 (2H, d), 7.88 (1H, d)
Process 2
Of 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-carbonyl) benzoylamino] propoxy] phenyl] acrylate methyl trifluoroacetate Composition
2.61 g (4.09 mmol) of benzyl (3R) -4- (5-cyano-2-iodophenoxy) -3- [4- (pyrrolidine-1-carbonyl) benzoylamino] butanoate, methyl 2-acetamidoacrylate 1.82 g (12.69 mmol), tris (2-methylphenyl) phosphine 773 mg (2.54 mmol), triethylamine 1.77 ml (12.69 mmol) and dimethylformamide 0.5 ml were dissolved in acetonitrile 14 ml, and palladium acetate 103 mg ( 0.42 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 4 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 30: 1, v / v), then dissolved in 4 ml of ethanol, and 20 ml of a 4N hydrogen chloride dioxane solution was added to room temperature. For 18 hours. Subsequently, the residue obtained by distilling off the solvent was dissolved in 20 ml of ethanol, 1.18 g (12.26 mmol) of ammonium carbonate was added, and the mixture was stirred at room temperature for 14 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 680 mg (0.94 mmol) Yield 23%
1H-NMR (DMSO-d6) δ: 1.16 (3H, t), 1.78-1.91 (4H, m), 1.95 (3H, s), 2.79 (2H, d), 3.34 (2H, t), 3.47 (2H , t), 3.64 (3H, s), 4.07 (2H, q), 4.25 (2H, t), 4.73 (1H, ddt), 7.31 (1H, s), 7.43 (1H, dd), 7.52 (1H, d), 7.58 (2H, d), 7.80 (1H, d), 7.84 (2H, d), 8.69 (1H, d), 9.09 (2H, s), 9.33 (2H, s), 9.65 (1H, br s)
Example 191
Synthesis of (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-carbonyl) benzoylamino] butanoic acid trifluoroacetate
Synthesis of methyl 2-acetamido-3- [4-amidino-2-[(2R) -3-carboxyl-2- [4- (pyrrolidine-1-carbonyl) benzoylamino] propoxy] phenyl] acrylate trifluoroacetate
Synthesis of 2-acetamido-3- [4-amidino-2-[(2R) -3-carboxyl-2- [4- (pyrrolidine-1-carbonyl) benzoylamino] propoxy] phenyl] acrylic acid trifluoroacetate
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-carbonyl) benzoylamino] propoxy] phenyl] methyl acrylate trifluoroacetate 105 mg (0.15 mmol) is dissolved in 6 ml of 6N hydrochloric acid and stirred at 40 ° C. for 2 hours and further at 60 ° C. for 1 hour. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the fraction of interest.
(3R) -4- [5-Amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-carbonyl) benzoylamino] butanoic acid trifluoroacetate
Yield 18.2 mg (0.03 mmol) Yield 20%
MS (ESI, M / Z) 525 (MH +)
1H-NMR (DMSO-d6) δ: 1.75-1.92 (4H, m), 2.70 (1H, d), 2.76 (1H, d), 3.35 (2H, d), 3.47 (2H, t), 4.24 (2H , d), 4.70 (1H, ddt), 6.81 (1H, s), 7.46 (1H, d), 7.49 (1H, s), 7.57 (2H, d), 7.88 (2H, d), 8.33 (1H, d), 9.15 (2H, m), 9.27 (2H, s)
Synthesis of methyl 2-acetamido-3- [4-amidino-2-[(2R) -3-carboxyl-2- [4- (pyrrolidine-1-carbonyl) benzoylamino] propoxy] phenyl] acrylate trifluoroacetate
Yield 32.8 mg (0.05 mmol) Yield 33%
MS (ESI, M / Z) 580 (MH +)
1H-NMR (DMSO-d6) δ: 1.76-1.91 (4H, m), 1.95 (3H, s), 2.73 (1H, d), 3.34 (2H, t), 3.48 (2H, t), 3.65 (3H , s), 4.26 (2H, t), 4.64-4.77 (1H, m), 7.32 (1H, s), 7.44 (1H, d), 7.55 (1H, s), 7.59 (2H, d), 7.73 ( 1H, d), 7.88 (2H, d), 8.67 (1H, d), 9.13 (2H, s), 9.33 (2H, s), 9.63 (1H, s)
Synthesis of 2-acetamido-3- [4-amidino-2-[(2R) -3-carboxyl-2- [4- (pyrrolidine-1-carbonyl) benzoylamino] propoxy] phenyl] acrylic acid trifluoroacetate
Yield 13.2 mg (0.02 mmol) Yield 13%
MS (ESI, M / Z) 566 (MH +)
1H-NMR (DMSO-d6) δ: 1.77-1.91 (4H, m), 1.94 (3H, s), 2.76 (2H, d), 3.35 (2H, t), 3.47 (2H, t), 4.27 (2H , d), 4.63-4.76 (1H, m), 7.36 (1H, s), 7.41 (1H, dd), 7.53 (1H, d), 7.57 (2H, d), 7.69 (1H, d), 7.86 ( 2H, d), 8.70 (1H, d), 9.19 (2H, s), 9.33 (2H, s), 9.50 (1H, s)
Example 192
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (piperidyl-4-oxy) benzoylamino] propoxy] phenyl] acrylate methyl ditrifluoroacetate Synthesis of
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (piperidyl-4-oxy) benzoylamino] propoxy] phenyl] acrylate ethyl ditrifluoroacetate Synthesis of
Process 1
Synthesis of ethyl 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoate
Ethyl 4-hydroxybenzoate (1.7 g, 10.2 mmol), 1-t-butoxycarbonyl-4-hydroxypiperidine (1.76 g, 9.3 mmol), and triphenylphosphine (2.44 g, 9.3 mmol) were added to tetrahydrofuran (40 ml). After dissolution, 1.62 g (9.3 mmol) of diethyl azodicarboxylate was added at room temperature and stirred overnight. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 1.57 g (4.5 mmol) Yield 44%
1H-NMR (CDCl3) δ: 1.38 (3H, t), 1.50 (9H, s) 1.70-1.80 (2H, m), 1.90-2.00 (2H, m), 3.30-3.41 (2H, m), 3.63- 3.75 (2H, m), 4.35 (2H, q), 4.55 (1H, m), 6.90 (2H, d), 8.00 (2H, d)
Process 2
Synthesis of 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoic acid
847 mg (2.43 mmol) of ethyl 4- (1-t-butoxycarbonyl-4-piperidyloxy) benzoate was dissolved in 50 ml of ethanol, 5 ml of 1N sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated and treated according to a conventional method using ethyl acetate as an extraction solvent to obtain the title compound.
Yield 697 mg (2.2 mmol) Yield 92%
1H-NMR (CDCl3) δ: 1.50 (9H, s), 1.70-2.00 (4H, m), 3.30-3.40 (2H, m), 3.65-3.75 (2H, m), 4.60 (1H, s), 6.95 (2H, d), 8.05 (2H, d)
Process 3
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (piperidyl-4-oxy) benzoylamino] propoxy] phenyl] acrylate methyl ditrifluoroacetate Synthesis of
(LR) -1-Benzyloxycarbonylmethyl-2- (5-cyano-2-iodophenoxy) ethylammonium chloride 1.33 g (2.81 mmol), 4- (1-t-butoxycarbonyl-4-piperidyloxy) 1.10 g (3.10 mmol) of benzoic acid, 419 mg (3.10 mmol) of 1-hydroxybenzotriazole and 0.86 ml (6.19 mmol) of triethylamine were dissolved in 30 ml of dichloromethane, and 1- (3-dimethylamino was dissolved under ice cooling. Propyl) -3-ethylcarbodiimide hydrochloride (593 mg, 3.10 mmol) was added and stirred for 10 minutes, followed by stirring at room temperature for 16 hours. Water was added to stop the reaction, and a crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequently, this was dissolved in 15 ml of acetonitrile, 1.21 g (8.43 mmol) of methyl 2-acetamidoacrylate, 513 mg (1.69 mmol) of tris (2-methylphenyl) phosphine, 1.17 ml (8.43 mmol) of triethylamine. , 0.5 ml of dimethylformamide was added. Subsequently, 69 mg (0.28 mmol) of palladium acetate was added at room temperature, and the mixture was stirred at 100 ° C. for 1 hour. Further, 30 mg (0.12 mmol) of palladium acetate was added, and the mixture was stirred at 100 ° C. for 4 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 30: 1, v / v), dissolved in 5 ml of ethanol, added with 30 ml of 4N hydrogen chloride in dioxane and room temperature. For 20 hours. Subsequently, the residue obtained by evaporating the solvent was dissolved in 20 ml of ethanol, 4.0 g (41.63 mmol) of ammonium carbonate was added, and the mixture was stirred at room temperature for 58 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 514 mg (0.61 mmol) Yield 22%
1H-NMR (DMSO-d6) δ: 1.16 (3H, t), 1.72-1.89 (2H, m), 1.95 (3H, s), 2.04-2.17 (2H, m), 2.79 (2H, d), 3.03 -3.18 (2H, m), 3.20-3.32 (2H, m), 3.66 (3H, s), 4.04 (2H, q), 4.23 (2H, d), 4.66-4.79 (1H, m), 7.06 (2H , d), 7.28 (1H, s), 7.44 (1H, dd), 7.53 (1H, d), 7.73 (1H, d), 7.81 (2H, d), 8.46 (1H, d), 9.18 (2H, s), 9.34 (2H, s), 9.67 (1H, br s) and 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (piperidyl-4) simultaneously -Oxy) benzoylamino] propoxy] phenyl] ethyl acrylate ditrifluoroacetate was also obtained.
Yield 104 mg (0.12 mmol) Yield 4%
1H-NMR (DMSO-d6) δ: 1.16 (3H, t), 1.19 (3H, t), 1.72-1.89 (2H, m), 1.96 (3H, s), 2.04-2.17 (2H, m), 2.78 (2H, d), 3.03-3.18 (2H, m), 3.20-3.32 (2H, m), 3.66 (3H, s), 4.08 (2H, q), 4.11 (2H, q), 4.22 (2H, d ), 4.66-4.79 (1H, m), 7.06 (2H, d), 7.29 (1H, s), 7.44 (1H, dd), 7.52 (1H, d), 7.75 (1H, d), 7.82 (2H, d), 8.46 (1H, d), 9.20 (2H, s), 9.33 (2H, s), 9.65 (1H, br s)
Example 193
(3R) -4- [5-Amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (1- (1-iminoethyl) piperidyl-4-oxy) benzoylamino] butanoic acid Synthesis of trifluoroacetate
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (piperidyl-4-oxy) benzoylamino] propoxy] phenyl] acrylate methyl ditrifluoroacetate 510 mg (0.61 mmol) was dissolved in 10 ml of ethanol, 1.70 ml (12.18 mmol) of triethylamine and 752 mg (6.09 mmol) of ethyl acetimidate hydrochloride were added, and the mixture was stirred at room temperature for 19 hours. The residue obtained by distilling off the solvent is dissolved in 14 ml of 6N hydrochloric acid and stirred at 70 ° C. for 4 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 325 mg (0.48 mmol) Yield 78%
MS (ESI, M / Z) 568 (MH +)
1H-NMR (DMSO-d6) δ: 1.70-1.87 (2H, m), 2.02-2.15 (2H, m), 2.29 (3H, s), 2.68 (1H, d), 2.74 (1H, d), 3.48 -3.58 (2H, m), 4.11-4.28 (2H, m), 4.60-4.72 (1H, m), 4.81 (1H, br s), 6.80 (1H, s), 7.07 (2H, d), 7.45 ( 1H, d), 7.48 (1H, s), 7.82 (2H, d), 8.33 (1H, d), 8.62 (1H, s), 9.14 (2H, s), 9.17 (1H, s), 9.26 (2H , s)
Example 194
Of 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-sulfonyl) benzoylamino] propoxy] phenyl] acrylate methyl trifluoroacetate Composition
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-sulfonyl) benzoylamino] propoxy] phenyl] acrylic acid ethyl trifluoroacetate Composition
Process 1
Synthesis of 4- (pyrrolidine-1-sulfonyl) benzoic acid
1.0 ml (12 mmol) of pyrrolidine was dissolved in 33 ml of piperidine, and 2.21 g (10 mmol) of 4-chlorosulfobenzoic acid was added under ice cooling, followed by stirring for 30 minutes and further stirring at room temperature for 30 minutes. The residue obtained by distilling off the solvent was suspended in 30 ml of 3N aqueous hydrochloric acid, and treated according to a conventional method using dichloromethane as an extraction solvent to obtain the title compound.
Yield 2.33 g (9.13 mmol) Yield 91%
1H-NMR (DMSO-d6) δ: 1.04-1.11 (4H, m), 2.55-2.64 (4H, m), 7.34 (2H, d), 7.55 (2H, d)
Process 2
Of 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-sulfonyl) benzoylamino] propoxy] phenyl] acrylate methyl trifluoroacetate Composition
(1R) -1-Benzyloxycarbonylmethyl-2- (5-cyano-2-iodophenoxy) ethylammonium chloride 1.50 g (3.17 mmol), 4- (pyrrolidine-1-sulfonyl) benzoic acid 891 mg (3. 49 mmol), 472 mg (3.49 mmol) of 1-hydroxybenzotriazole and 0.97 ml (6.98 mmol) of triethylamine were dissolved in 31 ml of dichloromethane, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added under ice cooling. 669 mg (3.49 mmol) of salt was added and stirred for 10 minutes, followed by stirring at room temperature for 17 hours. Water was added to stop the reaction, and a crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequently, this was dissolved in 12 ml of acetonitrile, 1.36 g (9.51 mmol) of methyl 2-acetamidoacrylate, 579 mg (1.90 mmol) of tris (2-methylphenyl) phosphine, 1.33 ml (9.51 mmol) of triethylamine. , 0.5 ml of dimethylformamide was added. Next, 78 mg (0.32 mmol) of palladium acetate was added at room temperature, and the mixture was stirred at 100 ° C. for 1 hour. Further, 35 mg (0.14 mmol) of palladium acetate was added, and the mixture was stirred at 100 ° C. for 3 hours. Again, 700 mg (4.89 mmol) of methyl 2-acetamidoacrylate, 250 mg (0.82 mmol) of tris (2-methylphenyl) phosphine, 3 ml (21.5 mmol) of triethylamine, and 33 mg (0.13 mmol) of palladium acetate were added at 100 ° C. And further stirred for 2.5 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 30: 1, v / v), dissolved in 3 ml of ethanol, 30 ml of 4N hydrogen chloride in dioxane was added and room temperature was added. For 22 hours. Subsequently, the residue obtained by distilling off the solvent was dissolved in 30 ml of ethanol, 2.0 g (20.82 mmol) of ammonium carbonate was added, and the mixture was stirred at room temperature for 39 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 486 mg (0.64 mmol) Yield 20%
1H-NMR (DMSO-d6) δ: 1.17 (3H, t), 1.61-1.68 (4H, m), 1.94 (3H, s), 2.81 (2H, d), 3.12-3.29 (4H, m), 4.08 (2H, q), 4.21 (1H, dd), 4.28 (1H, dd), 4.76 (1H, br s), 7.29 (2H, s), 7.44 (1H, dd), 7.53 (1H, d), 7.72 (1H, d), 7 90 (2H, d), 8.00 (2H, d), 8.86 (1H, d), 9.11 (2H, s), 9.33 (2H, s), 9.67 (1H, br s)
Simultaneously ethyl 2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-sulfonyl) benzoylamino] propoxy] phenyl] acrylate trifluoroacetate Was also obtained.
Yield 207 mg (0.27 mmol) Yield 8%
1H-NMR (DMSO-d6) δ: 1.15 (3H, t), 1.17 (3H, t), 1.61-1.68 (4H, m), 1.95 (3H, s), 2.82 (2H, d), 3.12-3.29 (4H, m), 4.08 (4H, q), 4.21 (1H, dd), 4.29 (1H, dd), 4.76 (1H, br s), 7.29 (2H, s), 7.43 (1H, dd), 7.51 (1H, d), 7.74 (1H, d), 790 (2H, d), 8.01 (2H, d), 8.87 (1H, d), 9.08 (2H, s), 9.33 (2H, s), 9.64 (1H, br s)
Example 195
Synthesis of (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-sulfonyl) benzoylamino] butanoic acid trifluoroacetate
2-acetamido-3- [4-amidino-2-[(2R) -3-ethoxycarbonyl-2- [4- (pyrrolidine-1-sulfonyl) benzoylamino] propoxy] phenyl] methyl acrylate
269 mg (0.35 mmol) of trifluoroacetate salt is dissolved in 14 ml of 6N hydrochloric acid and stirred at 70 ° C. for 4 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and water containing 0.1% (v / v) trifluoroacetic acid. The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 146 mg (0.22 mmol) Yield 62%
MS (ESI, M / Z) 561 (MH +)
1H-NMR (DMSO-d6) δ: 1.58-1.70 (4H, m), 2.71 (1H, dd), 2.75 (1H, dd), 3.12-3.20 (4H, m), 4.20-4.30 (2H, m) , 4.64-4.75 (1H, m), 6.80 (1H, s), 7.46 (1H, d), 7.47 (1H, s), 7.90 (2H, d), 8.02 (2H, d), 8.33 (1H, d ), 9.03 (2H, s), 9.27 (2H, s)
Example 196: N- [4- [1-acetimidoyl-4-piperidyloxy] phenyl] -N- [2- (3-amidinophenoxy) ethyl] sulfamoyl acetic acid Synthesis of ditrifluoroacetate salt
Step 1 Synthesis of 1-t-butoxycarbonyl-4- (4-nitrophenoxy) piperidine
1-t-Butoxycarbonyl-4-hydroxypiperidine (3.02 g, 15.0 mmol) obtained by subjecting 4-hydroxypiperidine to t-butoxycarbonylation using di-t-butyldicarbonate by a conventional method, 4-nitrophenol 2.09 g (15.0 mmol) and 4.72 g (18.0 mmol) of triphenylphosphine are dissolved in 50 ml of tetrahydrofuran, and 7.84 g (18.0 mmol) of diethyl azodicarboxylate (40% toluene solution) is added at room temperature. Stir overnight. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 2.74 g (8.5 mmol) Yield 57%
H-NMR (CDCl3) δ 1.50 (9H, s), 1.75-1.86 (2H, m), 1.92-2.03 (2H, m), 3.36-3.43 (2H, m), 3.67-3.75 (2H, m) , 4.58-4.64 (1H, m), 6.98 (2H, d), 8.20 (2H, d)
Step 2 Synthesis of 1-t-butoxycarbonyl-4- (4-aminophenoxy) piperidine
Dissolve 2.74 g (8.5 mmol) of 1-t-butoxycarbonyl-4- (4-nitrophenoxy) piperidine in 20 ml of ethanol, add 20 mg of 10% palladium on carbon, add 3 atmospheres at room temperature under a hydrogen atmosphere of 1 atm. Stir. Palladium on carbon was removed by suction filtration, and the filtrate was once concentrated and then treated according to a conventional method using dichloromethane as an extraction solvent to obtain the title compound.
Yield 2.59 g (8.02 mmol) Yield 94%
H-NMR (CDCl3) δ 1.47 (9H, s), 1.63-1.75 (2H, m), 1.82-1.93 (2H, m), 3.22-3.32 (2H, m), 3.68-3.78 (2H, m) , 4.71-4.80 (1H, m), 6.63 (2H, d), 6.76 (2H, d)
Step 3 Synthesis of 3- (2-bromoethoxy) benzonitrile
0.71 ml (10.0 mmol) of 2-bromoethanol, 1.43 g (12.0 mmol) of 3-cyanophenol and 3.15 g (12.0 mmol) of triphenylphosphine were dissolved in 100 ml of tetrahydrofuran, and diethyl azodicarboxylate (40 % Toluene solution) 5.22 g (12.0 mmol) was added at room temperature and stirred overnight. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 1.63 g (7.2 mmol) Yield 72%
H-NMR (CDCl3) δ3.67 (2H, t), 4.32 (2H, t), 7.14-7.19 (2H, m), 7.28 (1H, d), 7.40 (1H, dd)
Step 4 Synthesis of 3- [2-[[4- (1-t-butoxycarbonyl-4-piperidyloxy) phenyl] amino] ethoxy] benzonitrile
616 mg (1.91 mmol) of 1-t-butoxycarbonyl-4- (4-aminophenoxy) piperidine, 432 ml (1.91 mmol) of 3- (2-bromoethoxy) benzonitrile, 634 mg (3.82 mmol) of potassium iodide It melt | dissolved in 20 ml of dimethylformamide, 2.64 g (19.1 mmol) of potassium carbonate was added, and it stirred at room temperature for 14 hours. After distilling off the solvent under reduced pressure, the residue was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain a crude product. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 334 mg (0.76 mmol) Yield 40%
H-NMR (CDCl3) δ1.48 (9H, s), 1.63-1.78 (2H, m), 1.81-1.96 (2H, m), 3.22-3.32 (2H, m), 3.52 (2H, t), 3.66 -3.76 (2H, t), 4.17 (2H, t), 4.23-4.31 (1H, m), 6.63 (2H, d), 6.82 (2H, d), 7.14 (1H, dd), 7.16 (1H, d ), 7.26 (1H, dt), 7.38 (1H, dd)
Step 5 Synthesis of ethyl sulfoacetate
Sulfoacetic acid (2.21 g, 15.8 mmol) was suspended in ethanol (30 ml) and heated to reflux at 80 ° C. for 5 hours. The solvent was distilled off to obtain the title compound.
Yield 2.15 g (12.8 mmol) Yield 81%
H-NMR (CDCl3) δ1.33 (3H, t), 4.07 (2H, s), 4.27 (2H, q)
Step 6 Synthesis of ethyl chlorosulfonylacetate
1.43 g (8.50 mmol) of ethyl sulfoacetate was added to 4.6 ml (51.02 mmol) of phosphorus oxychloride, and the mixture was heated to reflux at 100 ° C. for 5 hours. The solvent was distilled off to obtain the title compound.
Yield 1.50 g (8.04 mmol) Yield 95%
H-NMR (CDCl3) δ1.38 (3H, t), 4.38 (2H, q), 4.60 (2H, s)
Step 7 Synthesis of ethyl N- [4- (1-t-butoxycarbonyl-4-piperidyloxy) phenyl] -N- [2- (3-cyanophenoxy) ethyl] sulfamoyl acetate
3- [2-[[4- (1-t-butoxycarbonyl-4-piperidyloxy) phenyl] amino] ethoxy] benzonitrile (334 mg, 0.76 mmol), triethylamine (2.79 ml, 20 mmol) in dichloromethane (10 ml) and pyridine (10 ml) Then, 1.50 g (8.04 mmol) of ethyl chlorosulfonylacetate was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 299 mg (0.51 mmol) Yield 67%
H-NMR (CDCl3) δ1.34 (3H, t), 1.47 (9H, s), 1.69-1.81 (2H, m), 1.87-1.99 (2H, m), 3.35 (2H, ddd), 3.69 (2H , ddd), 3.98 (2H, s), 4.06 (2H, t), 4.09 (2H, t), 4.30 (2H, q), 4.44-4.52 (1H, m), 6.92 (2H, d), 7.01 ( 1H, t), 7.06 (1H, ddd), 7.24 (1H, dt), 7.34 (1H, d), 7.39 (2H, d)
Step 8 N- [4- [1-acetimidoyl-4-piperidyloxy] phenyl] -N- [2- (3-amidinophenoxy) ethyl] sulfamoylacetic acid Synthesis of ditrifluoroacetate
299 mg (0.51 mmol) of ethyl N- [4- (1-t-butoxycarbonyl-4-piperidyloxy) phenyl] -N- [2- (3-cyanophenoxy) ethyl] sulfamoyl acetate was dissolved in 3 ml of ethanol, 10 ml of 4N hydrogen chloride in dioxane was added and stirred at room temperature for 20 hours. Subsequently, the residue obtained by distilling off the solvent was dissolved in 15 ml of ethanol, 1.5 g (15.6 mmol) of ammonium carbonate was added, and the mixture was stirred at room temperature for 55 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) Elution was performed with a mixed solvent of acetonitrile and acetonitrile, and the desired amidino-form fraction was lyophilized. The obtained solid was dissolved in 15 ml of ethanol, 0.84 ml (6.0 mmol) of triethylamine and 370 mg (3.0 mmol) of ethyl acetimidate hydrochloride were sequentially added, and the mixture was stirred at room temperature for 18 hours. Subsequently, the residue obtained by distilling off the solvent was dissolved in 14 ml of 6N hydrochloric acid and stirred at 40 ° C. for 5 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 144 mg (0.19 mmol) Yield 38%
MS (ESI, m / z) 518 (MH +)
H-NMR (DMSO-d6) δ 1.70-1.85 (2H, m), 2.01-2.14 (2H, m), 2.29 (3H, s), 3.45-3.57 (2H, m), 3.69-3.83 (2H, m), 4.04 (4H, dd), 4.18 (2H, s), 4.72 (1H, br s), 7.05 (2H, d), 7.20 (1H, dd), 7.31 (1H, t), 7.35 (2H, d), 7.39 (1H, dd), 7.50 (1H, t), 8.62 (1H, s), 9.16 (1H, s), 9.22 (2H, s), 9.28 (2H, s)
Example 197: Synthesis of (3R) -3- (3-amidinophenylcarbamoyl) -3- (4-dimethylcarbamoylbenzoylamino) propionate benzyl trifluoroacetate
1.7 g (5.2 mmol) of Nt-butoxycarbonyl-D-aspartic acid-β-benzyl ester and 1.2 g (5.7 mmol) of 3-aminobenzamidine dihydrochloride were dissolved in 35 ml of pyridine and ice-cooled. Then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2 g, 6.2 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography. Subsequently, the residue was dissolved in 30 ml of 4N hydrogen chloride in dioxane, followed by stirring at 0 ° C. for 1 hour and then at room temperature for 3 hours. The oily residue obtained by evaporating the solvent was dissolved in a mixed solvent of 30 ml of pyridine and 30 ml of dimethylformamide, and 995 mg (5.2 mmol) of 4-dimethylcarbamoylbenzoic acid (the compound of Step 1 of Example 56), 1- ( 3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1.2 g (6.2 mmol) was sequentially added, and the mixture was stirred at room temperature for 18 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 642 mg (1.03 mmol) Yield 20%
H-NMR (DMSO-d6) δ2.89 (3H, s), 2.94-3.02 (2H, m), 3.00 (3H, s), 5.05 (1H, dd), 5.13 (1H, d), 5.17 (1H , d), 7.28-7.38 (5H, m), 7.44 (1H, d), 7.51 (2H, d), 7.57 (1H, dd), 7.88 (1H, d), 7.93 (2H, d), 8.11 ( 1H, s), 8.99 (1H, d), 9.05 (2H, s), 9.32 (2H, s)
Example 198: Synthesis of (3R) -3- (3-amidinophenylcarbamoyl) -3- [4- (pyrrolidine-1-carbonyl) benzoylamino] propionic acid benzyl trifluoroacetate
1.7 g (5.2 mmol) of Nt-butoxycarbonyl-D-aspartic acid-β-benzyl ester and 1.2 g (5.7 mmol) of 3-aminobenzamidine dihydrochloride were dissolved in 35 ml of pyridine and ice-cooled. Then, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2 g, 6.2 mmol) was added, and the mixture was stirred at room temperature for 17 hours. The residue obtained by distilling off the solvent was purified by silica gel column chromatography. Subsequently, the residue was dissolved in 30 ml of 4N hydrogen chloride in dioxane, followed by stirring at 0 ° C. for 1 hour and then at room temperature for 3 hours. The oily residue obtained by distilling off the solvent was dissolved in a mixed solvent of 30 ml of pyridine and 30 ml of dimethylformamide, and 1.13 g of 4- (pyrrolidine-1-carbonyl) benzoic acid (Example ●●● -1) (5. 2 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1.2 g (6.2 mmol) were sequentially added and stirred at room temperature for 18 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 109 mg (0.17 mmol) Yield 3%
H-NMR (DMSO-d6) δ1.79-1.97 (4H, m), 2.94-3.02 (2H, m), 3.34-3.39 (2H, m), 3.44-3.52 (2H, m), 5.07 (1H, dd), 5.18 (2H, s), 7.29-7.38 (7H, m), 7.44 (1H, d), 7.59 (1H, dd), 7.87 (1H, d), 8.00 (2H, d), 8.11 (1H , s), 9.03 (2H, s), 9.08 (1H, d), 9.32 (2H, s)
Example 199: Synthesis of (3R) -3- (3-amidinophenylcarbamoyl) -3- [4- (pyrrolidine-1-carbonyl) benzoylamino] propionic acid trifluoroacetate
101 mg (0.16 mmol) of (3R) -3- (3-amidinophenylcarbamoyl) -3- (4-dimethylcarbamoylbenzoylamino) propionic acid trifluoroacetate salt is dissolved in 4 ml of concentrated hydrochloric acid and stirred at 40 ° C. for 5 hours. Stir. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 41 mg (0.08 mmol) Yield 47%
MS (ESI, m / z) 426 (MH +)
H-NMR (DMSO-d6) δ 2.89 (3H, s), 2.98 (1H, dd), 3.00 (3H, s), 3.27 (1H, dd), 4.86 (1H, ddd), 7.54 (2H, d ), 7.67 (1H, dd), 7.72 (1H, dd), 7.80 (1H, dd), 7.87 (1H, dd), 7.93 (2H, d), 9.16 (2H, s), 9.47 (2H, s) , 9.49 (1H, d)
Example 200: Synthesis of (3R) -3- (4-carboxybenzoylamino) -4- (3-amidinophenoxy) butanoic acid trifluoroacetate salt (byproduct of Example 119)
(3R) -3- (4-Amidinobenzoylamino) -4- (3-amidinophenoxy) butanoic acid 466 mg (0.73 mmol) of ditrifluoroacetate was dissolved in 10 ml of concentrated hydrochloric acid and stirred at 40 ° C. for 6 hours. . The residue obtained by distilling off hydrogen chloride was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 17 mg (0.034 mmol) Yield 5%
MS (ESI, m / z) 386 (MH +)
H-NMR (DMSO-d6) δ 2.75 (2H, d), 4.12 (1H, dd), 4.24 (1H, dd), 4.62-4.77 (1H, m), 7.32-7.42 (3H, m), 7.54 (1H, dd), 7.93 (2H, d), 8.02 (2H, d), 9.17 (2H, s), 9.28 (2H, s)
Example 201 3- [4-Amidino-2- [2- [4- [2- (pyridin-4-yl) ethyl] benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid ditrifluoroacetate Composition
Step 1 Synthesis of 4- [2- (pyridin-4-yl) ethyl] benzoic acid hydrochloride
4.80 g (16.8 mmol) of methyl 4- (diethoxyphosphorylmethyl) benzoate (Example 42, compound of Step 1) was dissolved in 100 ml of tetrahydrofuran, and 620 mg (15.5 mmol) of sodium hydride was dissolved under ice cooling. In addition, after stirring for 30 minutes, the mixture was returned to room temperature and stirred for 30 minutes. 1.38 g (12.9 mmol) of pyridine-4-aldehyde was added and stirred for 20 hours. A crude product obtained by treating in accordance with a conventional method using ethyl acetate as an extraction solvent was dissolved in 30 ml of methanol, added with 300 mg of 10% palladium-carbon, and stirred for 20 hours in the presence of hydrogen. After filtration through celite, the residue obtained by evaporating the solvent was dissolved in 30 ml of concentrated hydrochloric acid and stirred at 40 ° C. overnight. The crude title compound was obtained by distilling off the solvent.
Yield 2.7 g (0.008 mmol) 92%
Step 2 Synthesis of methyl 2-acetamido-3- [4-cyano-2- [2- [4- [2- (pyridin-4-yl) ethyl] benzoylamino] ethoxy] phenyl] acrylate trifluoroacetate
Methyl 2-acetamido-3- [4-cyano-2- (2-aminoethoxy) phenyl] acrylate hydrochloride 1.5 g (4.41 mmol) was dissolved in 50 ml of dimethylformamide, and 1.84 ml (13. 2 mmol), 1-hydroxybenzotriazole 655 mg (4.85 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 930 mg (4.85 mmol), 4- [2- (pyridin-4-yl) Ethyl] benzoic acid hydrochloride 1.10 g (4.85 mmol) was added and stirred overnight at room temperature. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. The obtained crude product was subjected to reversed-phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and containing a 0.1% trifluoroacetic acid (v / v) mixed solvent of water and acetonitrile. The title compound was obtained by elution and lyophilizing the fraction of interest.
Yield 800 mg (1.56 mmol) Yield 35%
H-NMR (DMSO-d6) δ1.96 (3H, s), 2.82-2.98 (4H, m), 3.76 (3H, s), 3.78 (2H, dt), 4.30 (2H, t), 7.02 (2H , dd), 7.10 (2H, d), 7.17 (2H, d), 7.32 (1H, d), 7.42 (2H, br), 7.63 (2H, d), 8.42 (2H, d)
Step 3 Synthesis of 3- [4-Amidino-2- [2- [4- [2- (pyridin-4-yl) ethyl] benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid ditrifluoroacetate
2-acetamido-3- [4-cyano-2- [2- [4- [2- (pyridin-4-yl) ethyl] benzoylamino] ethoxy] phenyl] methyl acrylate 800 mg (1.56 mmol) ) Was dissolved in 1 ml of ethanol and 5 ml of a dioxane solution containing 4N hydrogen chloride and stirred for 3 nights. After the solvent was distilled off, the residue was dissolved in 5 ml of ethanol, and 443 mg of ammonium carbonate was added and stirred overnight. After the solvent was distilled off, the residue was dissolved in 20 ml of concentrated hydrochloric acid and stirred at 40 ° C. for 3 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 70 mg (0.10 mmol) Yield 13%
MS (ESI, m / z) 475 (MH +)
H-NMR (DMSO-d6) δ 2.90-3.29 (4H, m), 3.69 (2H, dt), 4.25 (2H, s, keto form), 4.27 (2H, t), 6.82 (1H, s, enol form), 7.33 (2H, d), 7.37-7.49 (2H, m), 7.66 (2H, d), 7.78 (2H, d), 8.33 (1H, d), 8.67 (2H, d), 8.71 (1H , t), 9.08 (2H, br), 9.27 (2H, br)
Example 202: 2- (2R)-(4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoic acid ditrifluoroacetate salt
Step 1 Synthesis of 2- (2R) mi-t-butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl
5 g (15 mmol) of Nt-butoxycarbonyl-D-glutamic acid-α-benzyl ester and 2.1 g (15 mmol) of triethylamine were dissolved in 75 ml of tetrahydrofuran, and 1.43 ml (15 mmol) of ethyl chloroformate was added with ice cooling for 20 minutes. Stir. The generated precipitate was removed by suction filtration, and 5 g of ice and 0.57 g (15 mmol) of sodium borohydride were added to the filtrate under ice cooling, followed by stirring for 1.5 hours. 30 ml of 1N hydrochloric acid was added thereto, and the mixture was further stirred at room temperature for 1 hour. The residue obtained by treating with ethyl acetate as an extraction solvent according to a conventional method and evaporating the solvent was purified by silica gel chromatography to obtain the title compound.
Yield 1.67 g (5.2 mmol) Yield 35%
H-NMR (CDCl3) δ1.40 (9H, s), 1.60-2.10 (4H, m), 3.60 (2H, t), 4.40 (1H, m), 5.20 (3H, m), 7.40 (5H, m ).
Step 2 Synthesis of 2- (2R) mi-t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoic acid benzyl ester
2- (2R) -t-butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl 6.77 g (21 mmol) is dissolved in tetrahydrofuran 105 ml, 3-cyanophenol 2.74 g (23 mmol), triphenylphosphine 6.6 g ( 25 mmol) and 10 g (23 mmol) of diethyl azodicarboxylate (40% toluene solution) were added and stirred at room temperature for 1 hour. The residue obtained by evaporating the solvent was treated according to a conventional method using ethyl acetate as an extraction solvent, and the residue obtained by evaporating the solvent was purified by silica gel chromatography to obtain the title compound.
Yield 4.79 g (11.3 mmol) Yield 54%
H-NMR (CDCl3) δ1.42 (9H, s), 1.70-2.10 (4H, m), 3.95 (2H, t), 4.40 (1H, m), 5.10 (1H, br), 5.20 (2H, m ), 7.06-7.10 (2H, m), 7.23 (1H, d), 7.35 (5H, m)
Step 3 2- (2R)-(4-Amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoic acid ethyl ester Synthesis of ditrifluoroacetate
2- (2R) -t-butoxycarbonylamino-5- (3-cyanophenoxy) pentanoic acid benzyl ester (4.79 g, 11.3 mmol) is dissolved in 48 ml of a dioxane solution containing 4N hydrogen chloride and stirred at room temperature for 2 hours. did. The de-butoxycarbonyl compound obtained by distilling off the solvent was stirred in 57 ml of dichloromethane, and 1.6 g (11.3 mmol) of 4-cyanobenzoic acid, 1.68 g (12.4 mmol) of 1-hydroxybenzotriazole (containing water). , 3.5 ml (24.8 mmol) of triethylamine was added. Under ice cooling, 2.4 g (12.4 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added and stirred overnight. The crude product of the condensate was obtained by treating in accordance with a conventional method using ethyl acetate as an extraction solvent. To this crude product, 5 ml of dioxane and 4 ml of ethanol containing 30% hydrogen chloride (W / V) 4 ml of a dioxane solution containing 4N hydrogen chloride were added and stirred overnight. After the solvent was distilled off, the mixture was stirred overnight at room temperature in 50 ml of an ethanol solution containing 10% ammonia (w / v). 25% of the residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 187 mg (0.29 mmol) Yield 18.2%
MS (ESI, m / z) 426 (MH +), 424 (MH-).
H-NMR (DMSO-d6) δ 1.20 (3H, t), 1.80-2.10 (4H, m), 4.10-4.20 (4H, m), 4.50 (1H, m), 7.30 (1H, d), 7.40 (2H, m), 7.55 (1H, t) 7.95 (2H, d), 8.05 (2H, d), 9.10 (1H, d), 9.20 (2H, br), 9.30 (2H, br), 9.38 (2H , br), 9.45 (2H, br).
Example 203: 2- (2R)-(4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoic acid ethyl ditrifluoroacetate
Step 1 Ethyl 2- (2R)-(4-amidinobenzoylamino) -5- (3-amidinophenoxy) pentanoate Synthesis of ditrifluoroacetate
2- (2S)-(4-Amidino-benzoylamino) -5- (3-amidinophenoxy) -pentanoic acid ethyl ester 1.9 g (4.46 mmol) of ditrifluoroacetate in concentrated hydrochloric acid at 40 ° C. Stir for hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 347 mg (0.55 mmol) Yield 20%
MS (ESI, m / z) 398 (MH +), 396 (MH-).
H-NMR (DMSO-d6) δ1.80-2.10 (4H, m), 4.13 (2H, t), 4.50 (1H, m), 7.30 (1H, d), 7.40 (1H, d), 7.40 (1H , s), 7.52 (1H, t), 7.95 (2H, d), 8.10 (2H, d), 9.00 (1H, d), 9.20 (2H, br), 9.38 (2H, br), 9.40 (2H, br), 9.52 (2H, br).
Example 204: 4- (3-amidinophenoxy) -3-[[1- (pyridin-4-yl) -piperidine-4-carbonyl] amino] butyric acid Synthesis of ditrifluoroacetate
Step 1 Synthesis of 1- (pyridin-4-yl) -piperidine-4-carboxylic acid chloride
1- (Pyridin-4-yl) -piperidine-4-carboxylic acid hydrochloride 7 g (34 mmol) was stirred in 340 ml of dichloromethane, 1 ml of dimethylformamide and 10.4 ml (109 mmol) of oxalyl dichloride were added, and the mixture was stirred at room temperature for 1 hour. . After the solvent was distilled off, the title compound was obtained by drying with a vacuum pump for 1 hour.
Yield 7.9 g (35 mmol)
Step 2 Synthesis of 4- (3-cyanophenoxy) -3-[[1- (pyridin-4-yl) -piperidine-4-carbonyl] amino] butyric acid benzyl ester
1- (Pyridin-4-yl) piperidine-4-carboxylic acid chloride 3.7 g (16.5 mmol), (3R) -3-amino-4- (3-cyanophenoxy) butyric acid benzyl ester hydrochloride 4 g (12 mmol) ) Was stirred in 60 ml of dichloromethane, and 5.95 ml (42.7 mmol) of triethylamine, 1 ml of dimethylformamide and 50 mg of 4-dimethylaminopyridine were added and stirred overnight. The reaction mixture was extracted with dichloromethane, washed with 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to reverse phase chromatography using octadodecyl group chemically bonded silica gel as a filler, and eluted with a mixed solvent of water and acetonitrile containing 0.1% of trifluoroacetic acid (v / v). The solvent of the target fraction was distilled off, 1N sodium hydroxide was added, and the mixture was treated according to a conventional method using dichloromethane as an extraction solvent to obtain the title compound.
Yield 1.58 g (3.17 mmol) Yield 19%
Step 3 4- (3-Amidinophenoxy) -3-[[1- (Pyridin-4-yl) -piperidine-4-carbonyl] amino] butyric acid Synthesis of ditrifluoroacetate
4- (3-cyanophenoxy) -3-[[1- (pyridin-4-yl) -piperidin-4-carbonyl] amino] butyric acid benzyl ester (1.58 g, 3.17 mmol) and ethanol (1.6 ml) were added to 4N. The mixture was stirred overnight in 16 ml of a dioxane solution containing hydrogen chloride. The solvent was distilled off, 10 ml of ethanol solution and 0.5 g of ammonium carbonate were added and stirred overnight, and the solvent was distilled off. The obtained residue was stirred in 3 ml of concentrated hydrochloric acid at 40 ° C. for 4 hours. The solvent was distilled off, and the resulting residue was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 594 mg (0.91 mmol) Yield 29%
MS (ESI, m / z) 426 (MH +)
H-NMR (DMSO-d6) δ 1.50-1.61 (2H, m), 1.70-1.90 (2H, m), 2.50-2.85 (3H, m), 3.15-3.30 (2H, m), 4.00-4.20 ( 2H, m), 4.15-4.30 (2H, m), 4.40 (1H, m), 7.20 (2H, d), 7.30 (1H, d), 7.41 (1H, s), 7.42 (1H, d), 7.53 (1H, t), 8.17 (1H, d), 8.22 (2H, d), 9.29 (2H, br), 9.38 (2H, br).
Example 205: Synthesis of 3- [4-amidino-2- [2- [4- (pyrrolidine-1-carbonyl) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid trifluoroacetate
Step 1 Synthesis of methyl 2-acetamido-3- [4-cyano-2- [2- [4- (pyrrolidine-1-carbonyl) benzoylamino] ethoxy] phenyl] acrylate
Methyl 2-acetamido-3- [4-cyano-2- (2-aminoethoxy) phenyl] acrylate hydrochloride 2.5 g (7.4 mmol) was dissolved in dimethylformaldehyde to give 4- (pyrrolidine-1-carbonyl). Benzoic acid 1.56 g (8.1 mmol), 1-hydroxybenzotriazole 1.1 g (8.1 mmol), triethylamine 1.53 ml, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1.55 g ( 8.1 mmol) was added and stirred at room temperature overnight. The residue obtained by evaporating the solvent was treated according to a conventional method using ethyl acetate as an extraction solvent, and the residue obtained by evaporating the solvent was washed with hexane and dried to obtain the title compound.
Yield 1.80 g (3.68 mmol) Yield 50%
H-NMR (DMSO-d6) δ 1.78-1.90 (4H, m), 1.95 (3H, s), 3.30-3.50 (4H, m), 3.60-3.65 (3H, s), 3.70 (2H, dt) , 4.30 (2H, t), 7.20 (1H, s), 7.41 (1H, d), 7.55-7.70 (4H, m), 7.85 (2H, d), 8.75 (1H, t), 9.65 (1H, s ).
Step 2 Synthesis of 3- [4-Amidino-2- [2- [4- (pyrrolidine-1-carbonylbenzoylamino] ethoxy] phenyl] -2-oxo-propionic acid trifluoroacetate
Methyl 2-acetamido-3- [4-cyano-2- [2- [4- (pyrrolidine-1-carbonyl) benzoylamino] ethoxy] phenyl] acrylate 1.80 g (3.68 mmol) and 1 ml ethanol 4N chloride The mixture was stirred overnight in 20 ml of dioxane containing hydrogen. After the solvent was distilled off, 20 ml of ethanol and 1.0 g of ammonium carbonate were added and stirred overnight. After distilling off the solvent, 20 ml of 6N hydrochloric acid was added and heated to reflux at 80 ° C. for 1.5 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 345 mg (0.59 mmol) Yield 16%
MS (ESI, m / z) 467 (MH +)
H-NMR (DMSO-d6) δ 1.75-1.95 (4H, m), 3.30-3.50 (4H, m), 3.72 (2H, dt), 430 (2H, t), 4.25 (2H, s, keto ), 6.81 (1H, s, enol), 7.35-7.50 (2H, m), 7.60 (2H, d), 7.89 (2H, d), 8.33 (1H, d), 8.85 (1H, br), 9.01 (2H, br), 9.27 (2H, br), 9.80 (1H, br, enol)
Example 206: 3- [4-Amidino-2- [2-[[1- (pyridin-4-yl) piperidin-4-carbonyl] amino] ethoxy] phenyl] -2-oxo-propionic acid ditrifluoroacetic acid Salt synthesis
Step 1 Synthesis of methyl 2-acetamido-3- [4-cyano-2- [2-[[1- (pyridin-4-yl) piperidin-4-carbonyl] amino] ethoxy] phenyl] acrylate trifluoroacetate
Methyl 2-acetamido-3- [4-cyano-2- (2-aminoethoxy) phenyl] acrylate hydrochloride 1.0 g (2.94 mmol), 1- (pyridin-4-yl) piperidine-4-carboxylic acid 0.79 g (3.24 mmol) of hydrochloride and 1.64 ml of triethylamine were stirred in dimethylformamide, and 1.51 g (3.24 mmol) of bromotripyrrolidinophosphonium hexafluorophosphate was added thereto under ice cooling, and then at room temperature. Stir overnight. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 360 mg (0.73 mmol) Yield 25%
H-NMR (DMSO-d6) δ 1.50-1.70 (2H, m), 1.75-1.90 (2H, m), 1.95 (3H, s), 2.50 (1H, m), 3.15-3.30 (2H, m) , 3.42 (2H, dt), 3.65 (3H, s), 4.10-4.22 (4H, m), 7.15-7.21 (3H, m), 7.44 (1H, d), 7.58 (1H, s), 7.68 (1H , d), 8.09 (1H, t), 8.21 (2H, d), 9.65 (1H, s)
Step 2 3- [4-Amidino-2- [2-[[1- (pyridin-4-yl) piperidin-4-carbonyl] amino] ethoxy] phenyl] -2-oxo-propionic acid of ditrifluoroacetate Composition
2-acetamido-3- [4-cyano-2- [2-[[1- (pyridin-4-yl) piperidin-4-carbonyl] amino] ethoxy] phenyl] acrylic acid methyl trifluoroacetate 360 mg (0. 73 mmol) and 0.5 ml of ethanol were stirred overnight in 10 ml of a dioxane solution containing 4N hydrogen chloride. The solvent was distilled off, 5 ml of ethanol and 0.21 g of ammonium carbonate were added, and the mixture was stirred overnight at room temperature. To the residue obtained by distilling off the solvent, 10 ml of 6N hydrochloric acid was added and heated to reflux at 80 ° C. for 1.5 hours. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 205 mg (0.30 mmol) Yield 41%
MS (ESI, m / z) 454 (MH +)
H-NMR (DMSO-d6) δ 1.50-1.70 (2H, m), 1.80-1.95 (2H, m), 2.60 (1H, m), 3.18-3.30 (2H, m), 3.43-3.60 (2H, m), 4.10-4.30 (4H, m), 6.80 (1H, s, enol), 7.18 (2H, d), 7.35-7.48 (2H, m), 8.22 (2H, d), 8.34 (1H, d 9.15 (2H, br), 9.30 (2H, br), 9.80 (1H, br, enol).
Example 207: Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (4-methoxybenzoyl) benzamide trifluoroacetate
Step 1 Synthesis of methyl 4- (4-methoxybenzoyl) benzoate
2.1 g (16 mmol) of aluminum chloride and 2,4 g (12 mmol) of terephthalic acid monomethyl ester chloride were stirred in 15 ml of dichloromethane under ice-cooling, and 1.0 g (9.3 mmol) of anisole was added thereto. Two hours later, the mixture was warmed to room temperature and stirred overnight. It was treated according to a conventional method using dichloromethane as an extraction solvent, and the solvent was distilled off. The obtained residue was purified by silica gel chromatography to obtain the title compound.
Yield 610 mg (2.3 mmol) Yield 25%
H-NMR (CDCl3) δ 3.90 (3H, s), 3.98 (3H, s), 6.89 (2H, d), 7.79 (2H, d), 7.81 (2H, d), 8.14 (2H, d)
Step 2 Synthesis of 4- (4-methoxybenzoyl) benzoic acid
610 mg (2.3 mmol) of methyl 4- (4-methoxybenzoyl) benzoate was stirred in 40 ml of ethanol, 6 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred for 3 days. After the reaction solution was distilled off, 1N hydrochloric acid was added, and the mixture was treated according to a conventional method using ethyl acetate as an extraction solvent to obtain the title compound.
Yield 313 mg (1.22 mmol) Yield 53%
H-NMR (DMSO-d6) δ 3.88 (3H, s), 7.11 (2H, d), 7.78 (2H, d), 7.78 (2H, d), 8.09 (2H, d).
Step 3 Synthesis of N- [2- (3-amidinophenoxy) ethyl] -4- (4-methoxybenzoyl) benzamide trifluoroacetate
150 mg (0.59 mmol) of 4- (4-methoxybenzoyl) benzoic acid, 128 mg (0.64 mmol) of 3- (2-aminoethoxy) benzonitrile hydrochloride, 87 mg (0.64 mmol) of 1-hydroxybenzotriazole, triethylamine 0 .1 ml of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 123 mg (0.64 mmol) was stirred in dichloromethane overnight. Dichloromethane was used as an extraction solvent and treated according to a conventional method. The obtained condensate crude product was added with 1 ml of ethanol in 10 ml of dioxane containing 4N hydrogen chloride and stirred for 2 nights. The solvent was distilled off, and 0.2 g of ammonium carbonate and 10 ml of ethanol were added and stirred overnight. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 103 mg (0.19 mmol) Yield 32%
MS (ESI, m / z) 418 (MH +)
H-NMR (DMSO-d6) δ 3.70 (2H, dt), 3.85 (3H, s), 4.25 (2H, t), 7.10 (2H, d), 7.30-7.43 (3H, m), 7.54 (1H , t), 7.76 (2H, d), 7.76 (2H, d), 8.01 (2H, d), 8.95 (1H, t), 9.10 (2H, br), 9.30 (2H, br).
Example 208: Synthesis of ethyl (2S) -2- (4-dimethylcarbamoylbenzoylamino) -4- (3-amidinophenoxy) butyrate trifluoroacetate
(2S) -2-t-butoxycarbonylamino-4- (3-cyanophenoxy) butyric acid benzyl (compound of Step 1 of Example 91), 4-dimethylcarbamoylbenzoic acid as a raw material and Step 2 of Example 91; Similarly obtained benzyl (2S) -2- (4-dimethylcarbamoylbenzoylamino) -4- (3-cyanophenoxy) butyrate was treated in the same manner as in Step 6 of Example 1 to obtain the title compound.
MS (ESI, m / z) 441 (MH +)
H-NMR (DMSO-d6) δ 1.20 (3H, t), 2.25 (2H, m), 2.83 (3H, s), 3.00 (3H, s), 4.10-4.30 (4H, m), 4.70 (1H , m), 7.30 (1H, d), 7.35 (1H, s), 7.37 (1H, d), 7.50 (2H, d), 7.51 (1H, t), 7.92 (2H, d), 8.92 (1H, d), 9.05 (2H, br), 9.30 (2H, br).
Example 209: Synthesis of ethyl (2S) -2- (4-amidinobenzoylamino) -4- (3-amidinophenoxy) butyrate ditrifluoroacetate
The title compound was prepared by treating benzyl (2S) -2- (4-cyanobenzoylamino) -4- (3-cyanophenoxy) butyrate (compound of Step 2 of Example 91) in the same manner as Step 6 of Example 1. Got.
MS (ESI, m / z) 412 (MH +)
H-NMR (DMSO-d6) δ 1.20 (3H, t), 2.22-2.40 (2H, m), 4.10-4.30 (4H, m), 4.70 (1H, m), 7.31 (1H, d), 7.37 (1H, s), 7.39 (1H, d), 7.53 (1H, t), 7.92 (2H, d), 8.07 (2H, d), 9.12 (1H, d), 9.20 (2H, br), 9.28 ( 2H, br), 9.33 (2H, br), 9.43 (2H, br).
Example 210: Synthesis of (2S) -2- (4-carbamoylbenzoylamino) -4- (3-amidinophenoxy) butyric acid trifluoroacetate
The title compound was obtained as a byproduct of Step 3 of Example 91.
MS (ESI, m / z) 385 (MH +)
H-NMR (DMSO-d6) δ 2.20-2.40 (2H, m), 4.20 (2H, m), 4.65 (1H, m), 7.26-7.40 (3H, m), 7.51 (1H, br), 7.52 (1H, t), 7.95 (4H, s), 8.10 (1H, br), 8.87 (1H, d), 9.06 (2H, br), 9.29 (2H, br).
Example 211: 4- (3-Amidinophenoxy) -3- (3R)-[4- (pyrrolidine-1-carbonyl) benzoylamino] butyric acid Synthesis of trifluoroacetate
Step 1 Synthesis of 4- (1-pyrrolidylcarbonyl) benzoic acid
Terephthalic acid monomethyl ester chloride 29.0 g (0.146 mol), pyrrolidine 14.2 g (200 mmol) and triethylamine 21.0 g (208 mmol) were reacted in 350 ml of dichloromethane and treated in a conventional manner to give 4- (1-pyrrolidylcarbonyl). ) Methyl benzoate was obtained. 29.0 g of this ester was hydrolyzed in a mixed solvent of 12.0 g of sodium hydroxide, 70 ml of water, 70 ml of methanol and 70 ml of tetrahydrofuran, and the solvent was distilled off after completion of the reaction. 1N Hydrochloric acid was added and the mixture was treated according to a conventional method using dichloromethane as an extraction solvent to give the title compound.
Yield 23.7 g (108 mmol)
1H-NMR (DMSO-d6) δ: 1.75-1.90 (4H, m), 3.30-3.50 (4H, m), 7.62 (2H, d), 7.99 (2H, d), 13.14 (1H, br)
Step 2 Synthesis of 4- (3-cyanophenoxy) -3- (3R)-[4- (pyrrolidine-1-carbonyl) benzoylamino] butyric acid benzyl ester
(3R) -3-Amino-4- (3-cyanophenoxy) butyric acid benzyl ester hydrochloride (compound of Step 2 of Example 52) 1.8 g (5.2 mmol), 1-hydroxybenzotriazole (containing water) 703 mg (5.2 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 997 mg (5.2 mmol), triethylamine 526 mg (5.2 mmol), 4- (1-pyrrolidylcarbonyl) benzoic acid 14 g (5.2 mmol) was stirred in dichloromethane overnight. The reaction mixture was washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound.
Yield 1.82 g (3.56 mmol) Yield 69%
1H-NMR (CDCl3) δ: 1.85-2.05 (4H, m), 2.80-3.00 (2H, m), 3.35 (2H, t), 3.65 (2H, t), 4.10-4.25 (2H, m), 4.85 (1H, m), 5.20 (2H, s), 7.10 (1H, s), 7.12 (1H, d), 7.24-7.40 (7H, m), 7.54 (2H, d), 7.76 (2H, d)
Step 3 4- (3-Amidinophenoxy) -3- (3R)-[4- (pyrrolidine-1-carbonyl) benzoylamino] butyric acid Synthesis of trifluoroacetate
4- (3-Cyanophenoxy) -3- (3R)-[4- (pyrrolidine-1-carbonyl) benzoylamino] butyric acid 1.82 g (3.56 mmol) of benzyl ester and 3 ml of ethanol containing 4N hydrogen chloride Stir in dioxane for 2 days. To the residue obtained by distilling off the solvent, 20 ml of ethanol and 1.0 g of ammonium carbonate (purity 30% as ammonia) were added and stirred overnight. To the residue obtained by distilling off the solvent, 20 ml of concentrated hydrochloric acid was added and stirred at 40 ° C. overnight. The solvent was distilled off, and the resulting residue was subjected to reversed-phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) Elution was performed with a mixed solvent of acetonitrile and lyophilized, and the target fraction was lyophilized to obtain the title compound.
Yield 913 mg (1.65 mmol) Yield 46%
MS (ESI, m / z) 439 (MH +)
1H-NMR (DMSO-d6) δ: 1.70-1.90 (4H, m), 2.75 (2H, d), 3.35 (2H, t), 3.50 (2H, t), 4.05-4.30 (2H, m), 4.70 (1H, m), 7.32-7.43 (3H, m), 7.54 (1H, t), 7.60 (2H, d), 7.88 (2H, d), 8.64 (1H, d), 9.10 (2H, br), 9.28 (2H, br)
Example 212: 4- (3-Amidinophenoxy) -3- (3R)-(4-dimethylcarbamoyl-benzoylamino) butyric acid ethyl ester Synthesis of trifluoroacetate
4- (3-Cyanophenoxy)-(3R) -3- (4-dimethylcarbamoyl-benzoylamino) butyric acid benzyl ester (compound of Step 2 of Example 56) 1.87 g (3.98 mmol), ethanol 3 ml Stir in dioxane containing 4N hydrogen chloride for 2 days. To the residue obtained by distilling off the solvent, 20 ml of ethanol and 1.1 g of ammonium carbonate (purity 30% as ammonia) were added and stirred overnight. The title compound was obtained by subjecting the residue obtained by distilling off the solvent to reverse phase high performance liquid chromatography in the same manner as in the purification in Step 3 of Example 211.
Yield 895 mg (1.61 mmol) Yield 41%
MS (ESI, m / z) 441 (MH +)
1H-NMR (DMSO-d6) δ: 1.15 (3H, t), 2.80 (2H, d), 2.90 (3H, s), 3.00 (3H, s), 4.10 (2H, q), 4.00-4.25 (2H , m), 4.70 (1H, m), 7.30-7.40 (3H, m), 7.50 (2H, d), 7.54 (1H, t), 7.87 (2H, d), 8.65 (1H, d), 9.04 ( 2H, br), 9.27 (2H, br)
Example 213: 3- [4-Amidino-2- [2- [4- (N, N-dimethylamidino) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid ditrifluoroacetate
Step 1 Synthesis of [2- (5-cyano-2-iodophenoxy) ethyl] carbamic acid t-butyl ester
3-hydroxy-4-iodobenzonitrile (compound of Example 79, step 2), t-butyl (2-chloroethyl) carbamate (t-butyl (2-chloroethyl) carbamate is 2-chloroethylamine hydrochloride) And the title compound was obtained in the same manner as in Step 2 of Example 1.
1H-NMR (CDCl3) δ: 1.45 (9H, s), 3.62 (2H, dt), 4.10 (2H, t), 5.05 (1H, br), 6.96-7.06 (2H, m), 7.90 (1H, d )
Step 2 Synthesis of 2-acetamide-3- [2- (2-t-butoxycarbonylamino-ethoxy) -4-cyanophenyl] acrylic acid methyl ester
[2- (5-Cyano-2-iodophenoxy) ethyl] carbamic acid t-butyl ester 15.3 g (39.5 mmol), 2-acetamidoacrylic acid methyl ester 9.05 g (63.2 mmol), triethylamine 11 ml (79 mmol), 1.3 g of palladium (II) acetate, and 7.30 g (24.0 mmol) of tris (2-methylphenyl) phosphine were stirred overnight in 150 ml of acetonitrile. The solvent was distilled off, and the crude product obtained by purification by silica gel chromatography (ethyl acetate-hexane) was washed with a mixed solvent of hexane and hexane-ethyl acetate, and then dried in vacuo to give the title compound.
Yield 10.23 g (25.4 mmol) Yield 64%
1H-NMR (DMSO-d6) δ: 1.38 (9H, s), 1.95 (3H, s), 3.35 (2H, dt), 3.70 (3H, s), 4.10 (2H, t), 7.03 (1H, t ), 7.20 (1H, s), 7.43 (1H, d), 7.55 (1H, s), 7.68 (1H, d), 9.65 (1H, s)
Step 3 Synthesis of 2-acetamido-3- [2- (2-aminoethoxy) -4-cyanophenyl] acrylic acid methyl ester hydrochloride
2-Acetamide-3- [2- (2-t-butoxycarbonylamino-ethoxy) -4-cyanophenyl] acrylic acid methyl ester (7.75 g, 19.2 mmol) was added with 30 ml of dioxane and stirred, and 4N was added thereto. 80 ml of dioxane containing hydrogen chloride was added and stirred at room temperature for 1 hour. The title compound was obtained by evaporating the solvent and suspending the residue in ethyl acetate and collecting by filtration.
Yield 4.38 g (12.9 mmol) Yield 67%
1H-NMR (DMSO-d6) δ: 1.95 (3H, s), 3.25 (2H, dt), 3.70 (3H, s), 4.30 (2H, t), 7.28 (1H, s), 7.48 (1H, d ), 7.62 (1H, s), 7.70 (1H, d), 8.20 (3H, br), 9.75 (1H, s)
Step 4 Synthesis of 4- (N, N-dimethylamidino) benzoic acid hydrochloride
4- (N, N-dimethylamidino) benzoic acid ethyl ester (the compound of Step 1 of Example 7) was heated to reflux with 6N hydrochloric acid for 6 hours, and then the solvent was distilled off to obtain the title compound. 1H-NMR (DMSO-d6) δ: 2.95 (3H, s), 3.25 (3H, s), 7.75 (2H, d), 8.15 (2H, d), 9.25 (1H, br), 9.50 (1H, br )
Step 5 2-Acetamide-3- [4-cyano-2- [2- [4- (N, N-dimethylamidino) benzoylamino] ethoxy] phenyl] acrylic acid methyl ester Synthesis of trifluoroacetate
2-Acetamide-3- [2- (2-aminoethoxy) -4-cyanophenyl] acrylic acid methyl ester hydrochloride 3.54 g (10.4 mmol), 4- (N, N-dimethylamidino) benzoic acid hydrochloride 2.62 g (11.5 mmol), 3.5 ml (19.6 mmol) of diisopropylethylamine and 6.19 g (13.3 mmol) of bromo-tripyrrolidinophosphonium hexafluorophosphate were stirred overnight in dimethylformamide at room temperature. Dimethylformamide was distilled off under reduced pressure, extracted with ethyl acetate, washed with 1N sodium hydroxide and saturated brine, and dried over anhydrous magnesium sulfate. The title compound was obtained by subjecting the residue obtained by distilling off the solvent to reverse phase high performance liquid chromatography in the same manner as in the purification in Step 3 of Example 211.
Yield 1.0 g (1.73 mmol) Yield 17%
1H-NMR (DMSO-d6) δ: 1.95 (3H, s), 2.98 (3H, s), 3.22 (3H, s), 3.65 (3H, s), 3.70 (2H, dt), 4.30 (2H, t ), 7.21 (1H, s), 7.44 (1H, d), 7.62-7.74 (4H, m), 8.03 (2H, d), 8.88 (1H, t), 8.96 (1H, s), 9.35 (1H, s), 9.67 (1H, s)
Step 6 3- [4-Amidino-2- [2- [4- (N, N-dimethylamidino) benzoylamino] ethoxy] phenyl] -2-oxo-propionic acid Synthesis of ditrifluoroacetate
2-Acetamide-3- [4-cyano-2- [2- [4- (N, N-dimethylamidino) benzoylamino] ethoxy] phenyl] acrylic acid methyl ester trifluoroacetate 1.0 g (1.73 mmol) Then, 1.0 ml of ethanol was stirred in 20 ml of dioxane containing 4N hydrogen chloride at room temperature for 2 days. 20 ml of ethanol and 510 mg of ammonium carbonate were added to the residue obtained by distilling off the solvent, and the mixture was stirred at room temperature for 9 hours. The solvent was distilled off, 30 ml of 6N hydrochloric acid was added to the obtained residue, and the mixture was stirred at 80 ° C. for 1.5 hours. The title compound was obtained by subjecting the residue obtained by distilling off the solvent to reverse phase high performance liquid chromatography in the same manner as in the purification in Step 3 of Example 211.
Yield 397 mg (0.59 mmol) Yield 34%
MS (ESI, m / z) 440 (MH +)
1H-NMR (DMSO-d6) δ: 2.95 (3H, s), 3.25 (3H, s), 3.75 (2H, dt), 4.35 (2H, t), 4.20 (2H, s, keto form), 6.80 ( 1H, s, enol form), 7.38-7.48 (2H, m), 7.69 (2H, d), 8.04 (2H, d), 8.33 (1H, d), 8.95-9.40 (7H, m), 9.80 (1H , br, enol form)
Example 214: N- [2- (3-amidinophenoxy) ethyl] -4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzamide Synthesis of ditrifluoroacetate salt
Step 1 Synthesis of imidazoline-2-sulfonic acid
2-Imidazolinethione (3.32 g, 32.5 mmol), sodium molybdate dihydrate (250 mg, 1.03 mmol) and sodium chloride (750 mg) were stirred in 15 ml of water under ice-cooling, and the internal temperature increased from 4 ° C. 25 ml of 30% aqueous hydrogen peroxide was slowly added dropwise so that there was not. After completion of the dropwise addition, the mixture was stirred for 2 hours under ice-cooling, and then the reaction solution was filtered, and the precipitate was collected by filtration, washed with cold water and dried in vacuo to obtain the title compound.
Yield 1.47 g (9.81 mmol) Yield 30%
1H-NMR (DMSO-d6) δ: 3.85 (4H, s), 10.35 (1H, br)
Step 2 4-[(4,5-Dihydro-1H-imidazol-2-yl) amino] benzoic acid ethyl ester trifluoroacetate
Ethyl 4-aminobenzoate 991 mg (6.0 mmol), imidazoline-2-sulfonic acid 1.0 g (6.66 mmol), and triethylamine 1.35 g (13.3 mmol) were heated to reflux in 30 ml of acetonitrile overnight. The residue obtained by distilling off the solvent was extracted with ethyl acetate, washed with 1N sodium hydroxide and saturated brine, and the dry solvent was distilled off with anhydrous magnesium sulfate. The obtained residue was subjected to reverse phase high performance liquid chromatography in the same manner as in Step 3 of Example 211 to give the title compound.
Yield 86 mg (0.25 mmol) Yield 4%
1H-NMR (CD 3OD) δ: 1.40 (3H, t), 3.80 (4H, s), 4.38 (2H, q), 7.38 (2H, d), 8.10 (2H, d)
Step 3 N- [2- (3-Cyanophenoxy) ethyl] -4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzamide Synthesis of trifluoroacetic acid
4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoic acid ethyl ester 80 mg (0.23 mmol) of trifluoroacetic acid salt was heated to reflux in 10 ml of 6N hydrochloric acid for 5 hours, and the solvent was distilled off. 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoic acid hydrochloride was obtained.
4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoic acid hydrochloride 1H-NMR (DMSO-d6) δ: 3.70 (4H, s), 7.40 (2H, d), 8.00 ( 2H, d), 8.60 (2H, s)
To the total amount of carboxylic acid hydrochloride thus obtained, 2 ml of dimethylformamide, 3- (2-aminoethoxy) benzonitrile hydrochloride (compound H-NMR (DMSO-d6) δ3.20 (2H, t ), 4.25 (2H, t), 7.34 (1H, d), 7.46 (1H, d), 7.47 (1H, s), 7.54 (1H, t), 8.09 (3H, br)) 50 mg (0.25 mmol) 1-hydroxybenzotriazole (containing water) 34 mg (0.25 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 48 mg (0.25 mmol) and triethylamine 25 mg (0.25 mmol) were added at room temperature. And stirred overnight. The solvent was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to reverse phase high performance liquid chromatography in the same manner as in Step 3 of Example 211 to give the title compound.
Yield 67 mg (0.14 mmol) Yield 61%
1H-NMR (DMSO-d6) δ: 3.65 (2H, dt), 3.70 (4H, s), 4.20 (2H, t), 7.30-7.52 (6H, m), 7.95 (2H, d), 8.50 (2H , s), 8.75 (1H, t)
Step 4 N- [2- (3-Amidinophenoxy) ethyl] -4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzamide Synthesis of ditrifluoroacetic acid
N- [2- (3-cyanophenoxy) ethyl] -4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzamide trifluoroacetate 66 mg (0.14 mmol) and ethanol 0.5 ml Was stirred in 10 ml of dioxane containing 4N hydrogen chloride for 3 days. The solvent was distilled off, 10 ml of ethanol and 45 mg of ammonium carbonate were added and stirred for 2 days, and the solvent was distilled off. The residue was subjected to reverse phase high performance liquid chromatography in the same manner as in Step 3 of Example 211 to give the title compound.
Yield 58 mg (0.10 mmol) Yield 71%
MS (ESI, m / z) 367 (MH +)
1H-NMR (DMSO-d6) δ: 3.70 (2H, dt), 3.70 (4H, s), 4.20 (2H, t), 7.30-7.42 (5H, m), 7.54 (1H, t), 7.95 (2H , d), 8.60 (2H, s), 8.80 (1H, t), 9.19 (2H, br), 9.30 (2H, br), 10.90 (1H, s)
Example 215: 4- (3-amidinophenoxy) -3- (3R)-[4- (N, N-dimethylamidino) benzoylamino] butyric acid Synthesis of ditrifluoroacetate
Step 1 4- (3-Cyanophenoxy) -3- (3R)-[4- (N, N-dimethylamidino) benzoylamino] butyric acid Synthesis of trifluoroacetate
3.7 g (9.0 mmol) of (3R) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butyric acid benzyl ester (compound of Step 1 of Example 52) was stirred in 20 ml of dioxane, 10 ml of dioxane containing 4N hydrogen chloride was added and stirred at room temperature. After stirring at room temperature for 2 hours, the solvent was distilled off to obtain 20 ml of dimethylformamide, 2.47 g (10.8 ml) of 4- (N, N-dimethylamidino) benzoic acid hydrochloride, 1-hydroxybenzo Add 1.46 g (10.8 mmol) of triazole (hydrous), 2.07 g (10.8 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and 3.76 ml (27 mmol) of triethylamine at room temperature. Stir overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was subjected to reverse phase high performance liquid chromatography in the same manner as in Step 3 of Example 211 to give the title compound.
Yield 2.0 g (3.34 mmol) Yield 37%
1H-NMR (DMSO-d6) δ: 2.85 (2H, d), 3.00 (3H, s), 3.25 (3H, s), 4.20 (2H, m), 4.75 (1H, m), 5.10 (2H, s ), 7.28-7.52 (9H, m), 7.70 (2H, d), 8.02 (2H, d), 8.82 (1H, d), 9.06 (1H, br), 9.39 (1H, br)
Step 2 4- (3-Amidinophenoxy) -3- (3R)-[4- (N, N-dimethylamidino) benzoylamino] butyric acid Synthesis of ditrifluoroacetate
Step 3 of Example 211 using 518 mg (0.87 mmol) of 4- (3-cyanophenoxy) -3- (3R)-[4- (N, N-dimethylamidino) benzoylamino] butyric acid trifluoroacetate To give the title compound.
Yield 205 mg (0.32 mmol) Yield 37%
MS (ESI, m / z) 412 (MH +)
1H-NMR (DMSO-d6) δ: 2.75 (2H, d), 2.95 (3H, s), 3.25 (3H, s), 4.10-4.30 (2H, m), 4.70 (1H, m), 7.32-7.43 (3H, m), 7.54 (1H, t), 7.71 (2H, d), 8.04 (2H, d), 8.80 (1H, d), 9.00 (1H, br), 9.15 (2H, br), 9.30 ( 2H, br), 9.35 (1H, br)
Example 216: 3- (3R)-[N-Benzyl-N- (4-amidinobenzoyl) amino] -4- (3-amidinophenoxy) butyric acid Synthesis of ditrifluoroacetate
Step 1 Synthesis of 3- (3R) -benzylamino-4- (3-cyanophenoxy) butyric acid benzyl ester
(3R) -3-Amino-4- (3-cyanophenoxy) butyric acid benzyl ester A 1N aqueous sodium hydroxide solution was added to the hydrochloride and the mixture was extracted with dichloromethane. Furthermore, it wash | cleans with a saturated salt solution, The dry solvent is distilled off with anhydrous magnesium sulfate, 240 mg (0.77 mmol) which obtained (3R) -3-amino-4- (3-cyanophenoxy) butyric acid benzyl ester in methanol was obtained. The mixture was stirred, benzaldehyde (106 mg, 1.0 mmol) and sodium cyanoborohydride (58 mg, 0.92 mmol) were added thereto, and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added and methanol was distilled off under reduced pressure, 1N sodium hydroxide was added, and the mixture was extracted with ethyl acetate and washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and evaporated to give the title compound.
Yield 196 mg (0.49 mmol) Yield 64%
1H-NMR (CDCl3) δ2.70 (2H, d), 3.45 (1H, m), 3.85 (2H, d), 4.00 (2H, m), 5.15 (2H, s), 7.00-7.10 (2H, m ), 7.20-7.40 (12H, m)
Step 2 Synthesis of 3- (3R)-[N-benzyl-N- (4-cyanobenzoyl) amino] -4- (3-cyanophenoxy) butyric acid benzyl ester
190 mg (0.47 mmol) of 3- (3R) -benzylamino-4- (3-cyanophenoxy) butyric acid benzyl ester and 153 mg of triethylamine were stirred in 5 ml of dimethylformamide, and 70 mg of 4-cyanobenzoyl chloride was added thereto under ice cooling. 0.47 mmol) was added and stirred for 3 hours. Add 1N hydrochloric acid and extract with ethyl acetate. The extract was washed with 1N sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, evaporated, and purified by silica gel chromatography (ethyl acetate-hexane) to give the title compound.
Yield 148 mg (0.28 mmol) Yield 59%
1H-NMR (CDCl3) δ2.50-3.30 (2H, br), 3.70-4.80 (5H, br), 5.15 (2H, br), 6.80-7.70 (18H, br)
Step 3 Synthesis of 3- (3R)-[N-benzyl-N- (4-amidinobenzoyl) amino] -4- (3-amidinophenoxy) butyric acid ditrifluoroacetate
3- (3R)-[N-benzyl-N- (4-cyanobenzoyl) amino] -4- (3-cyanophenoxy) butyric acid benzyl ester 178 mg (0.38 mmol), ethanol 1 ml containing 4N hydrogen chloride. Stir for 4 days in 5 ml of dioxane. The residue obtained by distilling off the solvent was added with 10 ml of ethanol containing 10% ammonia (w / v) and stirred at room temperature for 5 days. The solvent was distilled off, and 10 ml of concentrated hydrochloric acid was stirred at 40 ° C. overnight. The title compound was obtained by subjecting the residue obtained by distilling off the solvent to the purification in Step 3 of Example 211 by reversed-phase high performance liquid chromatography.
Yield 48 mg (0.07 mmol) Yield 18%
MS (ESI, m / z) 474 (MH +)
1H-NMR (DMSO-d6) δ: 2.60-3.00 (2H, m), 3.80-4.70 (5H, m), 7.10-8.00 (13H, m), 9.10-9.50 (8H, br)
Example 217: Synthesis of N- [2- (3-amidinophenoxy) ethyl] -3- (E)-(4-chlorophenyl) acrylamide trifluoroacetate
Step 1 Synthesis of N- [2- (3-cyanophenoxy) ethyl] -3- (E)-(4-chlorophenyl) acrylamide
3- (2-aminoethoxy) benzonitrile hydrochloride 109 mg (0.55 mmol), 1-hydroxybenzotriazole (containing water) 85 mg (0.55 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride The title compound was obtained in the same manner as in Step 1 of Example 211 using 105 mg (0.55 mmol), triethylamine 61 mg (0.6 mmol), and p-chlorocinnamic acid 100 mg (0.55 mmol).
Yield 170 mg (0.52 mmol) Yield 95%
1H-NMR (CDCl3) δ 3.80 (2H, dt), 4.15 (2H, t), 6.05 (1H, br), 6.40 (1H, d), 7.15 (1H, d), 7.16 (1H, s), 7.27 (1H, d), 7.32mm 7.45 (5H, m), 7.61 (1H, d)
Step 2 Synthesis of N- [2- (3-amidinophenoxy) ethyl] -3- (E)-(4-chlorophenyl) acrylamide trifluoroacetate
The title compound was obtained in the same manner as in Step 6 of Example 1 using 165 mg (0.52 mmol) of N- [2- (3-cyanophenoxy) ethyl] -3- (E)-(4-chlorophenyl) acrylamide. .
Yield 108 mg (0.24 mmol) Yield 46%
MS (ESI, m / z) 344 (MH +)
1H-NMR (DMSO-d6) δ: 3.60 (2H, dt), 4.15 (2H, t), 6.70 (1H, d), 7.30-7.62 (9H, m), 8.40 (1H, t), 9.05 (2H , br), 9.30 (2H, br)
Example 218: Synthesis of N- [2- (3-amidinophenoxy) ethyl] -N-methyl-4-carbamoyl-benzamide trifluoroacetate
The title compound was obtained as a byproduct of Step 115 of Example 115.
Yield 21 mg (0.05 mmol) Yield 8%
MS (ESI, m / z) 341 (MH +)
1H-NMR (DMSO-d6) δ: 3.00 (3H, br), 3.60-4.40 (4H, br), 7.20-8.10 (10H, br), 9.30 (4H, br)
Example 219: 1- (4-Amidinobenzoyl)-(2R) -2-[(3-amidinophenoxy) methyl] pyrrolidine Synthesis of ditrifluoroacetate
Step 1 Synthesis of 1-t-butoxycarbonyl- (2R) -2-chloromethylpyrrolidine
(2R) -2-hydroxymethyl-pyrrolidine 500 mg (5 mmol), di-t-butyl dicarbonate 1.1 g (5 mmol), and triethylamine 500 mg (5 mmol) were stirred in dichloromethane at room temperature overnight. The reaction mixture was washed with 0.5N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in dichloromethane (20 ml), triethylamine (760 mg, 7.5 mmol) and mesyl chloride (860 mg, 7.5 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 5 hours. The residue obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent was dissolved in 5 ml of dimethylformamide, 1.06 g (25 mmol) of lithium chloride was added, and the mixture was stirred at 65 ° C. overnight. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 426 mg (1.94 mmol) Yield 39%
1H-NMR (CDCl3) δ1.50 (9H, s), 1.75-2.05 (4H, m), 3.30-3.80 (4H, m), 4.00 (1H, m)
Step 2 Synthesis of 1-t-butoxycarbonyl- (2R) -2-[(3-cyanophenoxy) methyl] pyrrolidine
430 mg (2 mmol) of 1-t-butoxycarbonyl- (2R) -2-chloromethylpyrrolidine is dissolved in 5 ml of dimethylamide, and 238 mg (2 mmol) of 3-hydroxybenzonitrile, 500 mg (3 mmol) of potassium iodide, 414 mg of potassium carbonate ( 3 mmol) was added and stirred at 90 ° C. for 3 days. The residue obtained by treating in accordance with a conventional method using ethyl acetate as an extraction solvent was purified by silica gel chromatography to obtain the title compound.
Yield 73 mg (0.24 mmol) Yield 12%
1H-NMR (CDCl3) δ 1.45 (9H, s), 1.82-2.08 (4H, m), 3.40 (2H, br), 3.90 (1H, m), 4.18 (2H, br), 7.10-7.30 (3H , m), 7.35 (1H, t)
Step 3 Synthesis of 1- (4-cyanobenzoyl)-(2R) -2-[(3-cyanophenoxy) methyl] pyrrolidine
70 mg (0.23 mmol) of 1-t-butoxycarbonyl- (2R) -2-[(3-cyanophenoxy) methyl] pyrrolidine was dissolved in a dioxane solution containing 4N hydrogen chloride and stirred at room temperature for 3 hours. The solvent was distilled off to obtain a crude product of the de-t-butoxycarbonyl compound. Dissolve 38 mg (0.25 mmol) of 4-cyanobenzoic acid in 3 ml of dimethylformamide, add 100 mg (1 mmol) of N-methylmorpholine and 25 mg (0.23 mmol) of ethyl chloroformate, and stir at 0 ° C. for 5 minutes. The crude product of t-butoxycarbonyl was added and stirred at room temperature for 2 hours. The title compound was obtained by treating in a conventional manner with ethyl acetate as the extraction solvent.
Yield 69.6 mg (0.21 mmol) Yield 91%
1H-NMR (CDCl3) δ: 1.82-2.22 (4H, m), 3.38-3.55 (2H, m), 4.10-4.63 (3H, m), 7.18-7.30 (3H, m), 7.39 (1H, t) 7.58 (2H, d), 7.73 (2H, d)
Step 4 1- (4-Amidinobenzoyl)-(2R) -2-[(3-amidinophenoxy) methyl] pyrrolidine Synthesis of ditrifluoroacetate
Starting from 69 mg (0.21 mmol) of 1- (4-cyanobenzoyl)-(2R) -2-[(3-cyanophenoxy) methyl] pyrrolidine as a starting material, the title compound was prepared in the same manner as in Step 6 of Example 1. Obtained.
Yield 22.7 mg (0.038 mmol) Yield 18%
MS (ESI, m / z) 366 (MH +)
1H-NMR (DMSO-d6) δ: 1.80-2.20 (4H, m), 3.30-3.55 (2H, m), 4.20-4.55 (3H, m), 7.36-7.58 (4H, m), 7.70 (2H, d), 7.89 (2H, d), 9.27-9.47 (8H, m)
Example 220: Synthesis of N- [2- (3-amidinophenoxy) ethyl] -6- (pyrrolidin-1-yl) nicotinamide trifluoroacetate
Step 1 Synthesis of 5-bromo-2- (pyrrolidin-1-yl) pyridine
2.95 g (28.6 mmol) of 2-amino-5-bromopyridine was dissolved in 40 ml of toluene, and 9.95 ml (57.2 mmol) of diisopropylethylamine, 6.15 g (28.6 mmol) of 1,4-dibromobutane, 4 100 mg (0.82 mmol) of-(dimethylamino) pyridine was added and stirred for 3 nights. The crude product was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 2.6 g (11.1 mmol) Yield 39%
1H-NMR (CDCl3) δ: 1.91-2.05 (4H, m), 3.32-3.46 (4H, m), 6.22 (1H, d), 7.44 (1H, dd), 8.12 (1H, d)
Step 2 Synthesis of 6- (pyrrolidin-1-yl) nicotinic acid methyl ester
2.6 g (11.1 mmol) of 5-bromo-2- (pyrrolidin-1-yl) pyridine was dissolved in 30 ml of dimethylformamide, 8.9 ml (220 mmol) of methanol, 3.06 ml (22 mmol) of triethylamine, palladium acetate (II ) 124 mg (0.5 mmol) and 2.7 g (11.1 mmol) of triphenylphosphine were added and stirred overnight at 70 ° C. in the presence of carbon monoxide. The crude product was obtained by treating according to a conventional method using ethyl acetate as an extraction solvent. Subsequent purification by silica gel column chromatography gave the title compound.
Yield 1.0 g (4.85 mmol) Yield 44%
1H-NMR (CDCl3) δ1.94-2.07 (4H, m), 3.40-3.56 (4H, m), 3.82 (3H, s), 6.29 (1H, d), 7.94 (1H, dd), 8.77 (1H , d)
Step 3 Synthesis of 6- (pyrrolidin-1-yl) nicotinic acid
1.0 g (4.85 mmol) of 6- (pyrrolidin-1-yl) nicotinic acid methyl ester was dissolved in 10 ml of concentrated hydrochloric acid and stirred at 40 ° C. overnight. The solvent was distilled off to obtain the hydrochloride of the title compound.
Yield 1.0 g (4.39 mmol) Yield 90%
Step 4 Synthesis of N- [2- (3-amidinophenoxy) ethyl] -6- (pyrrolidin-1-yl) nicotinamide trifluoroacetate
396 mg (1.74 mmol) of 6- (pyrrolidin-1-yl) nicotinic acid was dissolved in 10 ml of dichloromethane, 0.86 ml (6.18 mmol) of triethylamine, 306 mg (2.27 mmol) of 1-hydroxybenzotriazole, 1- (3 -Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 433 mg (2.27 mmol) and 3- (2-aminoethoxy) benzonitrile hydrochloride 449 mg (2.27 mmol) were added and stirred at room temperature overnight. The crude product of condensate was obtained by treating in accordance with a conventional method using dichloromethane as an extraction solvent. The obtained crude product was dissolved in 1 ml of ethanol and 5 ml of 4N hydrogen chloride in dioxane and stirred for 3 nights. After the solvent was distilled off, the residue was dissolved in 5 ml of ethanol, and 661 mg (8.49 mmol) of ammonium carbonate was added and stirred overnight. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 430 mg (0.74 mmol) Yield 43%
MS (ESI, m / z) 354 (MH +)
1H-NMR (DMSO-d6) δ: 1.91-2.05 (4H, m), 3.44-3.58 (4H, m), 3.63 (2H, dt), 4.33 (2H, t), 6.80 (1H, d), 7.29 -7.42 (3H, m), 7.54 (1H, dd), 8.12 (1H, dd), 8.51 (1H, d), 8.73 (1H, t), 9.20 (2H, br), 9.29 (2H, br)
Example 221: (3R) -4- (3-amidinophenoxy) -3- [4-[(1-acetimidoylpiperidin-4-yl) methyl] benzoylamino] butyric acid Synthesis of ditrifluoroacetate
(3R) -4- (3-Amidinophenoxy) -3- [4-[(piperidin-4-yl) methyl] benzoylamino] butyric acid ditrifluoroacetate (JP2 52-3) 10 mg (0.02 mmol) ) Was dissolved in 1 ml of ethanol, 10 mg (0.08 mmol) of ethylacetoimidate hydrochloride and 0.5 ml (3.3 mmol) of triethylamine were added, and the mixture was stirred overnight at room temperature. The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a packing material, and water containing 0.1% of trifluoroacetic acid (v / v) The title compound was obtained by elution with a mixed solvent of acetonitrile and lyophilization and lyophilization of the desired fraction.
Yield 6 mg (0.008 mmol) Yield 57%
MS (ESI, m / z) 480 (MH +)
1H-NMR (DMSO-d6) δ: 1.10-1.35 (2H, m), 1.58-1.75 (2H, m), 1.82-1.97 (1H, m), 2.23 (3H, s), 2.58 (2H, d) 2.70 (2H, d), 2.95-3.21 (2H, m), 3.62-3.92 (1H, m), 3.98-4.13 (2H, m), 4.24 (1H, dd), 4.68 (1H, ddt), 7.27 (2H, d), 7.32-7.43 (3H, m), 7.53 (1H, dd), 7.80 (2H, d), 8.47-8.65 (2H, m), 9.05 (1H, br), 9.21 (2H, br ), 9.27 (2H, br)
Example 222: (3R) -4- (3-amidinophenoxy) -3-[[4- [imino (pyrrolidin-1-yl) methyl] benzoyl] amino] butyric acid dihydrochloride
Step 1 Synthesis of 4- [imino (pyrrolidin-1-yl) methyl] benzoic acid hydrochloride
4-Cyanobenzoic acid (15.2 g, 103 mmol) was added to a solution of 200 ml of ethyl acetate solution containing 4N hydrogen chloride and 50 ml of ethanol, and the mixture was stirred for 5 days. After distilling off the solvent under reduced pressure, 100 ml of ethyl acetate was added to the obtained solid and stirred for 30 minutes, and then the solid was collected by filtration. The obtained solid was reacted for 2 days with 15.0 g (211 mmol) of pyrrolidine and 10.0 g (98.8 mmol) of triethylamine using 100 ml of ethanol as a solvent. After distilling off the solvent, 40 ml of 6N hydrochloric acid was added and reacted at 85 ° C. for 4 hours. After distilling off the solvent, 50 ml of 1N hydrochloric acid was added and stirred for 30 minutes, and then the solid was collected by filtration and further washed with 20 ml of ice water. The title compound was obtained by drying under reduced pressure.
Yield 7.67 g (30.1 mmol) Yield 29.2%
MS (ESI, m / z) 479 (MH +)
1H-NMR (DMSO-d6) δ: 1.78-1.92 (2H, m), 1.98-2.12 (2H, m), 3.23-3.43 (2H, m), 3.58-3.62 (2H, m), 7.78 (2H, d), 8.15 (2H, d), 9.18 (1H, bs), 9.45 (1H, bs) 13.41 (1H, bs)
Step 2 (3R) -4- (3-Amidinophenoxy) -3-[[4- [Imino (pyrrolidin-1-yl) methyl] benzoyl] amino] butyric acid Synthesis of ditrifluoroacetate
Dissolve 3.52 g (8.58 mmol) of benzyl (3R) -3-t-butoxycarbonylamino-4- (3-cyanophenoxy) butyrate (JP2 52-1) in 50 ml of ethyl acetate solution containing 4N hydrogen chloride. And stirred at room temperature for 4 hours. The solid obtained by distilling off the solvent was dissolved in a mixed solvent of 95 ml of dimethylformamide and 20 ml of dimethyl sulfoxide, and 1.74 g of 4- [imino- (pyrrolidin-1-yl) -methyl] benzoic acid hydrochloride was obtained. (6.83 mmol), 2.71 g (5.81 mmol) of bromotrispyrrolidinophosphonium hexafluoroborate and 3.85 g (8.26 mmol) of diisopropylethylamine were added and stirred at room temperature overnight. 400 ml of ethyl acetate was added, and the mixture was washed with 200 ml of 1N aqueous sodium hydroxide solution. The organic layer was separated and dried over magnesium sulfate. The crude product obtained by distilling off the solvent was subjected to reverse phase chromatography, and eluted with a mixed solvent of water and acetonitrile containing 0.1% trifluoroacetic acid (v / v). The condensate was obtained by freeze-drying. This condensate was reacted overnight with 35 ml of a dioxane solution containing 4N hydrogen chloride and 7 ml of ethanol. The residue obtained by distilling off the solvent was dissolved in 20 ml of ethanol, and 620 mg (6.59 mmol) of ammonium carbonate was added and allowed to react overnight. Further, the residue obtained by distilling off the solvent was reacted with 6N hydrochloric acid at 40 ° C. overnight. The residue obtained by distilling off the solvent was subjected to reverse phase chromatography, and eluted with a mixed solvent of water and acetonitrile containing 0.1% trifluoroacetic acid (v / v). Fractions of the desired product were lyophilized, 25 ml of dioxane containing 4N hydrogen chloride was added, and the mixture was stirred for 30 minutes. The solvent was distilled off, 25 ml of water was added thereto and lyophilized to obtain the title compound.
Yield 301 mg (0.590 mmol) Yield 6.9%
MS (ESI, m / z) 438 (MH +)
1H-NMR (DMSO-d6) δ: 1.80-1.91 (2H, m), 2.02-2.11 (2H, m), 2.73 (2H, d) 3.35 (2H, t), 3.57 (2H, d), 4.13 ( 1H, dd), 4.22 (1H, dd), 4.70 (1H, ddt), 7.34 (1H, d), 7.38-7.45 (2H, m), 7.53 (1H, dd), 7.74 (2H, d), 8.04 (2H, d), 8.83 (1H, d), 8.93 (1H, bs), 9.32 (2H, bs), 9.34 (2H, bs), 9.38 (1H, bs), 12.42 (1H, bs)
Example 223: Synthesis of N-[(1R) -2- (3-amidinophenoxy) -1-benzylethyl] -4- (pyrrolidine-1-carbonyl) benzamide trifluoroacetate
Step 1 Synthesis of t-butyl N-[(1R) -1-benzyl-2-chloroethyl] carbamate
After dissolving 6.01 g (36.4 mmol) of D-phenylalanine in a solution of 5.35 g (53.0 mmol) of triethylamine, 50 ml of tetrahydrofuran and 50 ml of water, 7.52 g (34.5 mmol) of di-tert-butyl dicarbonate And stirred at room temperature overnight to perform Nt-butoxycarbonylation. The solid obtained by processing according to a conventional method was dissolved in 80 ml of THF, 3.97 g (36.6 mmol) of ethyl chloroformate, 6.47 g (50.1 mmol) of diisopropylethylamine and 2.12 g (56.0 mmol) of sodium borohydride. ). Subsequently, 4.17 g (36.4 mmol) of methanesulfonyl chloride and 6.47 g (50.1 mmol) of diisopropylethylamine were used and reacted with 80 ml of dimethylformamide as a solvent. The title compound was obtained by reacting the residue obtained by treatment according to a conventional method using 8.42 g (199 mmol) of lithium chloride and 120 ml of dimethylformamide at 40 ° C. overnight.
Yield 8.52 g (31.6 mmol) Yield 86.8%
1H-NMR (CDCl3) δ: 2.82-2.94 (2H, m), 3.45 (1H, dd), 3.61 (1H, dd), 4.02-4.20 (1H, m), 4.85 (1H, d), 7.15-7.38 (5H, m)
Step 2 Synthesis of t-butyl N-[(1R) -1-benzyl-2- (3-cyanophenoxy) ethyl] carbamate
N-[(1R) -1-benzyl-2-chloroethyl] carbamate t-butyl 8.52 g (31.6 mmol), potassium carbonate 12.1 g (87.5 mmol) and 3-cyanophenol 5 g (41.9 mmol) Was reacted at 70 ° C. overnight using 120 ml of dimethylformamide as a solvent. The product was treated according to a conventional method and purified by silica gel column chromatography to obtain the title compound.
Yield 5.28 g (15.0 mmol) Yield 47.5%
1H-NMR (CDCl3) δ: 1.42 (9H, s), 2.95-3.02 (2H, m), 3.90 (2H, t), 4.85 (1H, d), 7.08-7.41 (9H, m)
Step 3 Synthesis of N-[(1R) -2- (3-amidinophenoxy) -1-benzylethyl] -4- (pyrrolidine-1-carbonyl) benzamide trifluoroacetate
Using 630 mg (1.79 mmol) of t-butyl N-[(1R) -1-benzyl-2- (3-cyanophenoxy) ethyl] carbamate and treating with 10 ml of a dioxane solution containing 4N hydrogen chloride, deprotection Got the body. 4- (Pyrrolidine-1-carbonyl) benzoic acid 720 mg (3.28 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1.55 g (8.09 mmol) 1-hydroxybenzotriazole 1.21 g (8.95 mmol) and 1.48 g (11.5 mmol) of diisopropylethylamine and 52 mg of 4-dimethylaminopyridine were condensed in dimethylformamide. Furthermore, the condensate was reacted for 6 days with 20 ml of a dioxane solution containing 4N hydrogen chloride and 2 ml of ethanol. The residue obtained by distilling off the solvent was dissolved in 20 ml of ethanol, and 1.0 g (10.6 mmol) of ammonium carbonate was added and reacted for 4 days. The residue obtained by distilling off the solvent was subjected to reverse phase chromatography, and eluted with a mixed solvent of water and acetonitrile containing 0.1% trifluoroacetic acid (v / v). Lyophilization gave the title compound.
Yield 325 mg (0.556 mmol) Yield 31.1%
1H-NMR (DMSO-d6) δ: 1.75-1.93 (4H, m), 2.92-3.15 (2H, m), 3.35 (2H, t), 3.44 (2H, t), 4.05-4.12 (2H, m) , 4.48-4.60 (1H, m), 7.18-7.55 (9H, m), 7.58 (2H, d), 7.82 (2H, d), 8.62 (1H, d), 9.15 (2H, bs), 9.27 (2H , bs)
Example 224: Synthesis of N-[(1R) -2- (3-amidinophenoxy) -1-benzylethyl] -4- (N, N-dimethylcarbamoyl) benzamide trifluoroacetate
N-[(1R) -1-benzyl-2- (3-cyanophenoxy) ethyl] carbamic acid Example using t-butyl 630 mg (1.79 mmol), 4- (N, N-dimethylcarbamoyl) benzoic acid The title compound was obtained according to a method similar to that described in Step 3 of 223.
Yield 417 mg (0.747 mmol) Yield 41.7%
1H-NMR (DMSO-d6) δ: 2.84 (3H, s), 3.00 (3H, s), 2.95-3.10 (2H, m), 3.10-3.22 (2H, m), 4.50-4.62 (1H, m) , 7.18-7.60 (9H, m), 7.46 (2H, d), 7.82 (2H, d), 8.62 (1H, d), 9.15 (2H, bs), 9.27 (2H, bs)
Example 225: Synthesis of N- [2- (3-amidinophenoxy) ethyl] -1- (dimethylaminocarbonyl) piperidine-4-carboxamide trifluoroacetate
Step 1 Synthesis of N- [2- (3-cyanophenoxy) ethyl] -1- (dimethylaminocarbonyl) piperidine-4-carboxamide
430 mg (1.58 mmol) of N- [2- (3-cyanophenoxy) ethyl] -piperidine-4-carboxamide (JP2 19-1) was dissolved in 1.6 ml of dimethylformamide, and 0.3 ml (2.06 mmol) of triethylamine was dissolved. ), 0.16 ml (1.74 mmol) of dimethylcarbamoyl chloride was added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. The title compound was obtained by treating in a conventional manner using ethyl acetate as an extraction solvent.
Yield 206 mg (0.60 mmol) Yield 38%
Step 2 Synthesis of N- [2- (3-amidinophenoxy) ethyl] -1- (dimethylcarbamoyl) piperidine-4-carboxamide trifluoroacetate
206 mg (0.60 mmol) of N- [2- (3-cyanophenoxy) ethyl] -1- (dimethylaminocarbonyl) piperidine-4-carboxamide was stirred in 3 ml of dioxane containing 4N hydrogen chloride, to which hydrogen chloride was added. After adding ethanol (3 ml) and stirring at room temperature for 1 day, the solvent was distilled off under reduced pressure. The residue obtained was dissolved in 5 ml of ethanol solution containing 10% ammonia (w / v) and stirred at room temperature for 1 day. . The residue obtained by distilling off the solvent was subjected to reverse phase high performance liquid chromatography using octadodecyl group chemically bonded silica gel as a filler, and contained 0.1% of trifluoroacetic acid (v / v). The title compound was obtained by elution with a mixed solvent of water and acetonitrile and lyophilizing the fraction of interest.
Yield 160 mg (0.34 mmol) Yield 56%
MS (ESI, m / z) 362 (MH +)
1H-NMR (DMSO-d6) δ: 1.50 (2H, ddd), 1.65 (2H, dd), 2.30 (1H, tt), 2.65 (2H, d), 2.70 (6H, s), 3.47 (2H, dd ), 3.52 (2H, d), 4.08 (2H, t), 7.30 (1H, d), 7.36 (1H, s), 7.38 (1H, d), 7.53 (1H, t), 8.09 (1H, t) , 9.24 (4H, d)
Example 226
The measurement of activated blood coagulation factor X inhibitory activity was carried out in the same manner as in Example 93, and the measurement of thrombin inhibitory activity was carried out in Example 94.
The anticoagulant activity was measured in the same manner as in Example 184. The results are summarized in Table 3.
Figure 0004103147
However, in the table, the compound of Example 181 is (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-carbonyl) benzoylamino. ] Butanoic acid represents trifluoroacetate.
This result shows that the benzamidine derivative of the present invention exhibits high inhibitory activity specific to activated blood coagulation factor X.
Hereinafter, structural formulas of the compounds of the present invention after Example 185 are shown.
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
Figure 0004103147
An anticoagulant containing the compound of the present invention or a salt thereof as an active ingredient exhibits an excellent anticoagulant action based on an activated blood coagulation factor X inhibitory action. Therefore, the compound of the present invention is useful for diseases in cerebrovascular disorders such as cerebral infarction, cerebral thrombus, cerebral embolism, transient cerebral ischemic attack (TIA), subarachnoid hemorrhage (vasospasm), acute and chronic myocardial infarction, unstable narrowing Diseases in ischemic heart diseases such as heart disease, coronary artery thrombolysis, diseases in pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism, peripheral arterial occlusion, deep vein thrombosis, generalized intravascular coagulation syndrome, and artificial vascular surgery And revascularization such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary revascularization (PTCR) It can be used as a prophylactic / therapeutic agent for subsequent re-occlusion and restenosis and thrombus formation during extracorporeal circulation.

Claims (25)

次の一般式（１）で表されるベンズアミジン誘導体またはその医薬的に許容しうる塩。
Figure 0004103147
［一般式（１）中、Ｌは下式（２）から（５）のいずれかの有機基を示す。
Figure 0004103147
（式（２）、（３）、（５）中、Ｗは、水素原子、炭素数１〜６のアルキル基、炭素数４〜１０のアリール基、炭素数５〜１２のアラルキル基もしくは炭素数２〜４のカルボキシルアルキルスルホニル基を示し、式（３）中、Ｄ又はＤ′のいづれか一方が一般式（１）中のＹとの結合を示し、もう一方が水素原子を示し、
式（２）中、Ｘは、水素原子、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基または置換基を有していてもよいメチル、エチルもしくはベンジル基を示し、置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜１０のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、アミジノピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、アミジノ基、ヒドロキシ基、ハロゲノ基、インドリル基もしくは炭素数１〜５のアルキル基があげられる。また式（２）中、ＸとＷは結合して環を構成してもよく、この場合−Ｗ−Ｘ−はエチレン基、トリメチレン基もしくはテトラメチレン基を示す。）
Ｌが式（２）または（３）のいずれかの有機基の場合、Ｖは、水素原子、置換基を有するフェニル又はベンゾイル基、置換基を有していてもよいベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、ピリジンカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示す。
Ｌが式（４）の有機基の場合、Ｖは、置換基を有するベンゾイル基、置換基を有していてもよい２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示す。Ｌが式（５）の有機基の場合、Ｖは置換基を有していても良い炭素数４から１０のアリール基を示す。
Ｌが式（２）〜（５）のいずれかの有機基の場合において、Ｖが置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数１〜３のアルコキシ基で置換されてもよい炭素数１〜８のアシル基、ハロゲノ基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数２〜７のアルコキシカルボニルアミノ基、炭素数１〜３のアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、アミノ基で置換されてもよい炭素数６〜９のアシルピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数２〜７のヒドロキシカルボニルアルキル基、炭素数３〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数１〜１０のアルコキシ基、ニトロ基、トリフルオロメチル基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数５〜１２のアリールアルキル基、ピペラジンカルボニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、ベンジルスルホニルアミノ基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペラジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、アミノエチルオキシ基、炭素数３〜６のジアルキルアミノスルホニル基、炭素数２〜４のジアルキルグアジニノ基が挙げられる。
Ｌが式（２）〜（４）のいずれかの有機基の場合には、或いはＶは次の式（６）の有機基を示す。
Figure 0004103147
（Ｒ1は水素原子、アルコキシカルボニル基もしくはメチル基のいずれかを表し、Ｒ2は水素原子、メチル基、ブチル基、ベンジル基、アミノブチル基、ヒドロキシカルボニルエチル基、ヒドロキシカルボニルプロピル基もしくはイミダゾリルメチル基のいずれかを表し、Ｒ3は水素原子もしくはピリジル基を示す。）
Ｙは下式（７）、（８）、（９）、（１０）または（１１）のいずれかを示す。
Figure 0004103147
（式（７）及び（８）中、ｎは１〜３の整数を示す。）
Ｚは水素原子、炭素数１〜６のアルキル基、ハロゲノ基または下式（１２−１）、（１２−２）、（１２−３）のいずれかを示す。
Figure 0004103147
（Ｒ4はカルボキシル基もしくは炭素数４〜１０のアリール基のいずれか、Ｒ5は炭素数１〜６のアルキル基、Ｒ6は水素原子、炭素数１〜６のアルキル基又は炭素数１〜７のアルコキシ基のいずれか、Ｒ7は水素原子又は炭素数１〜６のアルキル基のいずれかを示す。）］A benzamidine derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
Figure 0004103147
[In the general formula (1), L represents an organic group of any one of the following formulas (2) to (5).
Figure 0004103147
(Wherein, in formulas (2), (3) and (5), W represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 4 to 10 carbon atoms, an aralkyl group having 5 to 12 carbon atoms or a carbon number. 2 to 4 carboxylalkylsulfonyl groups, wherein in formula (3), either D or D ′ represents a bond to Y in general formula (1), the other represents a hydrogen atom,
In the formula (2), X represents a hydrogen atom, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a methyl, ethyl or benzyl group which may have a substituent. Are a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, an amidinopiperidyloxy group, an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, and a carbon number of 8 -14 alkoxycarbonylpiperidyloxy group, C6-8 piperidylalkyl group, C8-11 iminoalkylpiperidylalkyl group, C9-15 alkoxycarbonylpiperidylalkyl group, pyrrolidyloxy group, carbon number 6-9 iminoalkylpyrrolidyloxy groups, 7 carbon atoms 13 alkoxycarbonyl pyrrolidyl group, amidino group, hydroxy group, halogeno group, an alkyl group of indolyl group or C1-5 and the like. In formula (2), X and W may combine to form a ring, and in this case, -W-X- represents an ethylene group, trimethylene group or tetramethylene group. )
When L is an organic group represented by formula (2) or (3), V is a hydrogen atom, a phenyl or benzoyl group having a substituent, an optionally substituted benzenesulfonyl, or 2-naphthalenesulfonyl. , Camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, pyridinecarbonyl, phenylthiocarbonyl or benzimidoyl group or an optionally substituted carbon number 1-6 alkanesulfonyl groups are shown.
When L is an organic group of the formula (4), V is a benzoyl group having a substituent, an optionally substituted 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidini A ruaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, phenylthiocarbonyl or benzimidoyl group or an alkanesulfonyl group having 1 to 6 carbon atoms which may have a substituent is shown. When L is an organic group of the formula (5), V represents an aryl group having 4 to 10 carbon atoms which may have a substituent.
In the case where L is an organic group of any one of formulas (2) to (5), the substituent in the case where V has a substituent includes a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, carbon A mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an amidino group, a mono- or dialkylamidino group having 2 to 7 carbon atoms, an acyl group having 1 to 8 carbon atoms which may be substituted with an alkoxy group having 1 to 3 carbon atoms, halogeno Group, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, arylamino group having 4 to 6 carbon atoms, alkoxycarbonylamino group having 2 to 7 carbon atoms, aminoalkyl group having 1 to 3 carbon atoms, carbon number 2 to 7 mono- or dialkylaminoalkyl group, 4 to 10 carbon atoms N-alkyl-N-alkoxycarbonylaminoalkyl group, piperidyloxy group, C6-C9 acylpiperidyloxy group, C7-C10 iminoalkylpiperidyloxy group, C8-C14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, carbon number which may be substituted with mino group 6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C2-7 hydroxycarbonylalkyl group, C3-8 alkoxycarbonylalkyl group, C3-3 7 hydroxycarbonyl alkenyl group, C 4-8 alkoxycarbonyl alkenyl group, C 4-10 aryl group, C 6-12 aryl alkenyl group, C 1-10 alkoxy group, nitro group, tri Fluoromethyl group, alkyl group having 3 to 8 carbon atoms, arylsulfur having 4 to 10 carbon atoms Nyl group, arylalkyl group having 5 to 12 carbon atoms, piperazinecarbonyl group, iminoalkylpiperazinecarbonyl group having 7 to 10 carbon atoms, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, benzylsulfonylamino group, A piperidylalkyl group having 6 to 9 carbon atoms, an iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms, a piperazidenealkyl group having 6 to 9 carbon atoms, an iminoalkylpiperidenealkyl group having 8 to 12 carbon atoms, a guanidino group, Phosphono group, dialkoxyphosphoryl group having 2 to 9 carbon atoms, monoalkoxyhydroxyphosphoryl group having 1 to 4 carbon atoms, aminoethyloxy group, dialkylaminosulfonyl group having 3 to 6 carbon atoms, dialkyl group having 2 to 4 carbon atoms An azino group may be mentioned.
When L is an organic group of any one of formulas (2) to (4), or V represents an organic group of the following formula (6).
Figure 0004103147
(R 1 represents either a hydrogen atom, an alkoxycarbonyl group or a methyl group, and R 2 represents a hydrogen atom, a methyl group, a butyl group, a benzyl group, an aminobutyl group, a hydroxycarbonylethyl group, a hydroxycarbonylpropyl group or an imidazolylmethyl group. Any one of the groups, and R 3 represents a hydrogen atom or a pyridyl group.)
Y represents one of the following formulas (7), (8), (9), (10) or (11).
Figure 0004103147
(In formulas (7) and (8), n represents an integer of 1 to 3)
Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, or any one of the following formulas (12-1), (12-2), and (12-3).
Figure 0004103147
(R 4 is either a carboxyl group or an aryl group having 4 to 10 carbon atoms, R 5 is an alkyl group having 1 to 6 carbon atoms, R 6 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 to 1 carbon atoms. Any one of 7 alkoxy groups, R 7 represents either a hydrogen atom or an alkyl group having 1 to 6 carbon atoms)] 一般式（１）中、Ｌが式（２）から（５）のいずれかの有機基を示し、式（２）中、Ｗが、水素原子、炭素数１〜６のアルキル基、炭素数４〜１０のアリール基もしくは炭素数５〜１２のアラルキル基を示し、式（３）及び（５）中、Ｗは水素原子を示し、式（３）中、Ｄが一般式（１）中のＹとの結合を示し、Ｄ′が水素原子を示し、
Ｘが、水素原子、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基または置換基を有していてもよいメチル、エチルもしくはベンジル基を示し、置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、アミジノ基、ヒドロキシ基、ハロゲノ基、インドリル基もしくは炭素数１〜３のアルキル基があげられ、また式（２）中、ＸとＷは結合して環を構成してもよく、この場合−Ｗ−Ｘ−はエチレン基、トリメチレン基もしくはテトラメチレン基を示し、
Ｌが式（２）または（３）のいずれかの有機基の場合、Ｖは、水素原子、置換基を有するベンゾイル基、置換基を有していてもよいベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示し、
Ｌが式（４）の有機基の場合、Ｖは、置換基を有するベンゾイル基、置換基を有していてもよい２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニルもしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示し、Ｌが式（５）の有機基の場合、Ｖは置換基を有していても良い炭素数４から１０のアリール基を示し、
Ｌが式（２）〜（５）のいずれかの有機基の場合において、Ｖが置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数１〜８のアシル基、ハロゲノ基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数２〜７のアルコキシカルボニルアミノ基、炭素数１〜３のアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数２〜７のヒドロキシカルボニルアルキル基、炭素数３〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数１〜１０のアルコキシ基、ニトロ基、トリフルオロメチル基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数５〜１２のアリールアルキル基、ピペラジンカルボニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、ベンジルスルホニルアミノ基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペリジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、アミノエチルオキシ基が挙げられ、
Ｌが式（２）〜（４）のいずれかの有機基の場合には、或いはＶは式（６）の有機基を示し、
Ｙが式（７）、（８）、（９）、（１０）または（１１）のいずれかを示し、式（７）中、ｎは１又は２であり、式（８）中、ｎは１であり、
Ｚが水素原子、炭素数１〜６のアルキル基、ハロゲノ基または式（１２−１）のいずれかを示し、式（１２−１）中、Ｒ4はカルボキシル基もしくは炭素数４〜１０のアリール基のいずれかを示す、請求項１記載のベンズアミジン誘導体またはその医薬的に許容しうる塩。In general formula (1), L represents an organic group of any one of formulas (2) to (5), and in formula (2), W is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or 4 carbon atoms. 10 represents an aryl group having 10 to 10 carbon atoms or an aralkyl group having 5 to 12 carbon atoms, W in formulas (3) and (5) represents a hydrogen atom, and in formula (3), D represents Y in formula (1). D ′ represents a hydrogen atom,
X represents a hydrogen atom, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a methyl, ethyl or benzyl group which may have a substituent, and the substituent in the case of having a substituent includes a carboxyl group, carbon An alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, an alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, and a carbon number 6-8 piperidylalkyl groups, C8-11 iminoalkylpiperidylalkyl groups, C9-15 alkoxycarbonylpiperidylalkyl groups, pyrrolidyloxy groups, C6-9 iminoalkylpyrrolidyloxy groups, C7-13 alkoxycarbonylpyrrolidyloxy Group, amidino group, hydroxy group, halogeno group, indolyl group or alkyl group having 1 to 3 carbon atoms, and in formula (2), X and W may be combined to form a ring. -W-X- represents an ethylene group, trimethylene group or tetramethylene group;
When L is an organic group of either formula (2) or (3), V is a hydrogen atom, a benzoyl group having a substituent, an optionally substituted benzenesulfonyl, 2-naphthalenesulfonyl, camphor Sulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, phenylthiocarbonyl or benzimidoyl group or an optionally substituted alkane having 1 to 6 carbon atoms Represents a sulfonyl group,
When L is an organic group of the formula (4), V is a benzoyl group having a substituent, an optionally substituted 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidini A ruaminoacetyl, quinuclidinyl acetyl, indolecarbonyl, phenylthiocarbonyl or benzimidoyl group or an optionally substituted alkanesulfonyl group having 1 to 6 carbon atoms, wherein L is an organic group of the formula (5) In the case of a group, V represents an optionally substituted aryl group having 4 to 10 carbon atoms,
In the case where L is an organic group of any one of formulas (2) to (5), the substituent in the case where V has a substituent includes a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, carbon C2-C7 mono- or dialkylcarbamoyl group, amidino group, C2-C7 mono- or dialkylamidino group, C1-C8 acyl group, halogeno group, amino group, C1-C6 mono- or dialkyl Amino group, arylamino group having 4 to 6 carbon atoms, alkoxycarbonylamino group having 2 to 7 carbon atoms, aminoalkyl group having 1 to 3 carbon atoms, mono- or dialkylaminoalkyl group having 2 to 7 carbon atoms, carbon number 4 -10 N-alkyl-N-alkoxycarbonylaminoalkyl group, piperidyloxy group, C7-10 iminoalkylpiperidyloxy Group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, C6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C2-7 Hydroxycarbonylalkyl group, C3-C8 alkoxycarbonylalkyl group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, C4-C10 aryl group, carbon number 6-12 arylalkenyl groups, C1-C10 alkoxy groups, nitro groups, trifluoromethyl groups, C3-C8 alkyl groups, C4-C10 arylsulfonyl groups, C5-C12 Arylalkyl group, piperazine carbonyl group, iminoalkyl piperazine having 7 to 10 carbon atoms Rubonyl group, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl group having 6-9 carbon atoms, benzylsulfonylamino group, piperidylalkyl group having 6-9 carbon atoms, iminoalkylpiperidylalkyl group having 8-12 carbon atoms, 6-6 carbon atoms 9 piperididenealkyl groups, C8-12 iminoalkylpiperididenealkyl groups, guanidino groups, phosphono groups, C2-9 dialkoxyphosphoryl groups, C1-4 monoalkoxyhydroxyphosphoryl groups An aminoethyloxy group,
When L is an organic group of any one of formulas (2) to (4), or V represents an organic group of formula (6),
Y represents any one of the formulas (7), (8), (9), (10) or (11), and in the formula (7), n is 1 or 2, and in the formula (8), n is 1 and
Z represents any one of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, and formula (12-1), and in formula (12-1), R 4 is a carboxyl group or an aryl having 4 to 10 carbon atoms. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which shows any of the groups. 一般式（１）中、Ｖが置換基を有する場合の置換基が、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、カルバモイル基、アミジノ基、アセチル基、臭素原子、アミノ基、メチルアミノ基、ｔ−ブトキシカルボニルアミノ基、アミノメチル基、（メチルアミノ）メチル基、（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、３−ピロリジルオキシ基、１−ｔ−ブトキシカルボニル−３−ピロリジルオキシ基、２−カルボキシルエテニル基、２−（エトキシカルボニル）エテニル基、ジメチルカルバモイル基、Ｎ−エチル−Ｎ−メチルカルバモイル基、２−イミダゾリニル基、１−ピペリジンカルボニル基、Ｎ，Ｎ−ジメチルアミジノ基、２−（テトラヒドロピリミジニル）基、１−ピロリジンカルボニル基、２−（４−ピリジル）ビニル基、１−ピロール基、シクロヘキシルオキシ基、ジエチルアミノ基、２−（４−ピリジル）エチル基、イソプロピル基、１−ピロリジル基、ベンゾイル基、ベンゼンスルホニル基、ベンジル基、４−ピリジル基、ジメチルアミノ基、１−ピペリジニル基、フェノキシ基、１−ピペラジンカルボニル基、１−アセトイミドイル−４−ピペラジンカルボニル基、（４−ピリジル）アミノ基、メチルカルバモイル基、フェニル基、シクロヘキシル基、１−ピペラジンスルホニル基、１−アセトイミドイル−４−ピペラジンスルホニル基、４−（ピリジル）メチル基、４−ピペリジリデンメチル基、４−ピペリジルメチル基、１−アセトイミドイル−４−ピペリジリデンメチル基、１−アセトイミドイル−４−ピペリジルメチル基、２−イミダゾリル基、１−フェノキシカルボニル−４−ピペリジルオキシ基、モノエトキシヒドロキシホスホリル基、ジエトキシホスホリル基、塩素原子、１−（アミノアセチル）−４−ピペリジルオキシ基、トリフルオロメチル基、ベンジルスルホニルアミノ基、グアニジノ基、ホスホノ基もしくはアミノエチルオキシ基のいずれかである請求項２記載のベンズアミジン誘導体またはその医薬的に許容しうる塩。In the general formula (1), when V has a substituent, the substituent is a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a carbamoyl group, an amidino group, an acetyl group, a bromine atom, an amino group, a methylamino group, t -Butoxycarbonylamino group, aminomethyl group, (methylamino) methyl group, (Nt-butoxycarbonyl-N-methylamino) methyl group, 4-piperidyloxy group, 1-acetimidoyl-4-piperidyloxy group 3-pyrrolidyloxy group, 1-t-butoxycarbonyl-3-pyrrolidyloxy group, 2-carboxyl ethenyl group, 2- (ethoxycarbonyl) ethenyl group, dimethylcarbamoyl group, N-ethyl-N-methylcarbamoyl Group, 2-imidazolinyl group, 1-piperidinecarbonyl group, N, N-dimethylamidino 2- (tetrahydropyrimidinyl) group, 1-pyrrolidinecarbonyl group, 2- (4-pyridyl) vinyl group, 1-pyrrole group, cyclohexyloxy group, diethylamino group, 2- (4-pyridyl) ethyl group, isopropyl group, 1-pyrrolidyl group, benzoyl group, benzenesulfonyl group, benzyl group, 4-pyridyl group, dimethylamino group, 1-piperidinyl group, phenoxy group, 1-piperazinecarbonyl group, 1-acetimidoyl-4-piperazinecarbonyl group, (4-pyridyl) amino group, methylcarbamoyl group, phenyl group, cyclohexyl group, 1-piperazinesulfonyl group, 1-acetimidoyl-4-piperazinesulfonyl group, 4- (pyridyl) methyl group, 4-piperidylidenemethyl Group, 4-piperidylmethyl group, 1-acetimidyl -4-piperidylidenemethyl group, 1-acetimidoyl-4-piperidylmethyl group, 2-imidazolyl group, 1-phenoxycarbonyl-4-piperidyloxy group, monoethoxyhydroxyphosphoryl group, diethoxyphosphoryl group, chlorine atom 1- (aminoacetyl) -4-piperidyloxy group, trifluoromethyl group, benzylsulfonylamino group, guanidino group, phosphono group or aminoethyloxy group, or a benzamidine derivative according to claim 2 or a pharmaceutical thereof Acceptable salt. 一般式（１）中、Ｗが、水素原子、メチル基もしくはベンジル基のいずれかである請求項２記載のベンズアミジン誘導体またはその医薬的に許容しうる塩。The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 2, wherein, in the general formula (1), W is any one of a hydrogen atom, a methyl group and a benzyl group. 一般式（１）中、Ｘが置換基を有する場合の置換基が、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基、エタンスルホニルオキシ基、ブタンスルホニルオキシ基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、１−ベンジルオキシカルボニル−４−ピペリジルオキシ基、４−ピペリジルメチル基、（１−アセトイミドイル−４−ピペリジル）メチル基、１−アセトイミドイル−３−ピロリジルオキシ基、イソプロピル基、３−インドリル基もしくはヨウ素原子のいずれかである請求項２記載のベンズアミジン誘導体またはその医薬的に許容しうる塩。In the general formula (1), when X has a substituent, the substituent is carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, ethanesulfonyloxy group, butanesulfonyloxy group, 4-piperidyloxy group, 1-acetimide Yl-4-piperidyloxy group, 1-benzyloxycarbonyl-4-piperidyloxy group, 4-piperidylmethyl group, (1-acetimidoyl-4-piperidyl) methyl group, 1-acetimidoyl-3-pyrrolidyl The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 2, which is any one of an oxy group, an isopropyl group, a 3-indolyl group and an iodine atom. 一般式（１）中、Ｚが、水素原子、ヨウ素原子、メチル基、２−カルボキシル−２−オキソエチル基もしくは２−（２−フリル）−２−オキソエチル基のいずれかである請求項２記載のベンズアミジン誘導体またはその医薬的に許容しうる塩。The general formula (1), wherein Z is any one of a hydrogen atom, an iodine atom, a methyl group, a 2-carboxyl-2-oxoethyl group or a 2- (2-furyl) -2-oxoethyl group. A benzamidine derivative or a pharmaceutically acceptable salt thereof. 一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗが、水素原子、炭素数１〜６のアルキル基、炭素数４〜１０のアリール基もしくは炭素数５〜１２のアラルキル基を示し、
Ｘが、水素原子、カルボキシル基、メトキシカルボニル基、エトキシカルボニル基または置換基を有していてもよいメチル、エチルもしくはベンジル基を示し、置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基を示し、
Ｖが、水素原子、置換基を有するベンゾイル基、置換基を有していてもよいベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチルまたは置換基を有していてもよい炭素数１〜６のアルカンスルホニル基を示し、
Ｖが置換基を有する場合の置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜３のアミノアルキル基、炭素数２〜７のアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数３〜７のヒドロキシカルボニルアルキル基、炭素数４〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基が挙げられ、
或いはＶは式（６）の有機基を示し、（式（６）中、Ｒ1は水素原子、アルコキシカルボニル基又はメチル基を表し、Ｒ2はメチル基、ブチル基、ベンジル基、アミノブチル基、ヒドロキシカルボニルエチル基、ヒドロキシカルボニルプロピル基もしくはイミダゾリルメチル基のいずれかを表し、Ｒ3は水素原子を示す。）、
Ｙが式（７）、（８）、（９）、（１０）または（１１）のいずれかを示し、式（７）中、ｎは１又は２であり、式（８）中、ｎは１であり、
Ｚが水素原子、炭素数１〜６のアルキル基、ハロゲノ基または式（１２−１）のいずれかを示し、式（１２−１）中、Ｒ4はカルボキシル基もしくは炭素数４〜１０のアリール基のいずれかを示す、請求項１記載のベンズアミジン誘導体またはその医薬的に許容しうる塩。In general formula (1), L represents an organic group of formula (2), and in formula (2), W is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 4 to 10 carbon atoms, or carbon. Represents an aralkyl group of formula 5-12,
X represents a hydrogen atom, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group or a methyl, ethyl or benzyl group which may have a substituent, and the substituent in the case of having a substituent includes a carboxyl group, carbon An alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, an alkoxycarbonylpiperidyloxy group having 8 to 14 carbon atoms, and a carbon number 6-8 piperidylalkyl groups, C8-11 iminoalkylpiperidylalkyl groups, C9-15 alkoxycarbonylpiperidylalkyl groups, pyrrolidyloxy groups, C6-9 iminoalkylpyrrolidyloxy groups, C7-13 alkoxycarbonylpyrrolidyloxy It represents a group,
V is a hydrogen atom, a substituted benzoyl group, an optionally substituted benzenesulfonyl, 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclide. A diunimilacetyl or an optionally substituted alkanesulfonyl group having 1 to 6 carbon atoms;
Examples of the substituent when V has a substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an aminoalkyl group having 1 to 3 carbon atoms, an alkylaminoalkyl group having 2 to 7 carbon atoms, and 4 carbon atoms. C-10 N-alkyl-N-alkoxycarbonylaminoalkyl group, piperidyloxy group, C7-10 iminoalkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, carbon number 6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C3-7 hydroxycarbonylalkyl group, C4-8 alkoxycarbonylalkyl group, 3-3 carbon atoms 7 hydroxycarbonylalkenyl group, alkoxycarbonylalkoxy having 4 to 8 carbon atoms Include group,
Or V represents an organic group of formula (6), (in the formula (6), R 1 represents a hydrogen atom, an alkoxycarbonyl group or a methyl group, R 2 is a methyl group, butyl group, benzyl group, aminobutyl group , A hydroxycarbonylethyl group, a hydroxycarbonylpropyl group or an imidazolylmethyl group, and R 3 represents a hydrogen atom).
Y represents any one of the formulas (7), (8), (9), (10) or (11), and in the formula (7), n is 1 or 2, and in the formula (8), n is 1 and
Z represents any one of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, and formula (12-1), and in formula (12-1), R 4 is a carboxyl group or an aryl having 4 to 10 carbon atoms. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which shows any of the groups. 一般式（１）中、Ｖが置換基を有する場合の置換基がカルボキシル基、メトキシカルボニル基、エトキシカルボニル基、アミノカルボニル基、アミジノ基、アセチル基、臭素原子、アミノ基、メチルアミノ基、ｔ−ブトキシカルボニルアミノ基、アミノメチル基、（メチルアミノ）メチル基、（Ｎ−ｔ−ブトキシカルボニル−Ｎ−メチルアミノ）メチル基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、３−ピロリジルオキシ基、１−ｔ−ブトキシカルボニル−３−ピロリジルオキシ基、２−カルボキシルエテニル基、２−（エトキシカルボニル）エテニル基のいずれかである請求項７記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In the general formula (1), when V has a substituent, the substituent is carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, aminocarbonyl group, amidino group, acetyl group, bromine atom, amino group, methylamino group, t -Butoxycarbonylamino group, aminomethyl group, (methylamino) methyl group, (Nt-butoxycarbonyl-N-methylamino) methyl group, 4-piperidyloxy group, 1-acetimidoyl-4-piperidyloxy group The benzamidine derivative according to claim 7, wherein the benzamidine derivative is a 3-pyrrolidyloxy group, a 1-t-butoxycarbonyl-3-pyrrolidyloxy group, a 2-carboxylethenyl group, or a 2- (ethoxycarbonyl) ethenyl group. Its pharmaceutically acceptable salt. 一般式（１）中、Ｗが水素原子、メチル基、ベンジル基のいずれかである請求項７記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 7, wherein, in the general formula (1), W is any one of a hydrogen atom, a methyl group and a benzyl group. 一般式（１）中、Ｘが置換基を有する場合の置換基がカルボキシル基、メトキシカルボニル基、エトキシカルボニル基、エタンスルフォニルオキシ基、ブタンスルフォニルオキシ基、４−ピペリジルオキシ基、１−アセトイミドイル−４−ピペリジルオキシ基、１−ベンジルオキシカルボニル−４−ピペリジルオキシ基、４−ピペリジルメチル基、（１−アセトイミドイル−４−ピペリジル）メチル基、１−アセトイミドイル−３−ピロリジルオキシ基のいずれかである請求項７記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In the general formula (1), when X has a substituent, the substituent is carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, ethanesulfonyloxy group, butanesulfonyloxy group, 4-piperidyloxy group, 1-acetimidoyl. -4-piperidyloxy group, 1-benzyloxycarbonyl-4-piperidyloxy group, 4-piperidylmethyl group, (1-acetimidoyl-4-piperidyl) methyl group, 1-acetimidoyl-3-pyrrolidyloxy The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 7, which is any one of groups. 一般式（１）中、Ｚが水素原子、ヨウ素原子、メチル基、２−カルボキシル２−オキソエチル基、２−（２−フリル）−２−オキソエチル基のいずれかである請求項７記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。The benzamidine derivative according to claim 7, wherein, in the general formula (1), Z is any one of a hydrogen atom, an iodine atom, a methyl group, a 2-carboxyl-2-oxoethyl group, and a 2- (2-furyl) -2-oxoethyl group. Or a pharmaceutically acceptable salt thereof. 一般式（１）中、Ｌが式（２）又は式（４）の有機基を示し、式（２）中、Ｗが、水素原子又は炭素数１〜６のアルキル基を示し、
Ｘが、水素原子、炭素数２〜３のカルボキシアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数１〜８のアシル基、ハロゲノ基、アミノ基、炭素数１〜６のモノもしくはジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数２〜７のアルコキシカルボニルアミノ基、炭素数１〜３のアミノアルキル基、炭素数２〜７のモノもしくはジアルキルアミノアルキル基、炭素数４〜１０のＮ−アルキル−Ｎ−アルコキシカルボニルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、炭素数２〜７のヒドロキシカルボニルアルキル基、炭素数３〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数１〜１０のアルコキシ基、ニトロ基、トリフルオロメチル基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数５〜１２のアリールアルキル基、ピペラジンカルボニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、ピペラジンスルホニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、ベンジルスルホニルアミノ基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペリジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基、アミノエチルオキシ基、炭素数３〜６のジアルキルアミノスルホニル基、炭素数２〜４のジアルキルグアニジノ基が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが、水素原子、（１２-2-1）、（１２−３）のいずれかを示す、
Figure 0004103147
（Ｒ51は、水素原子または炭素数１〜６のアルキル基、Ｒ6は水素原子、炭素数１〜６のアルキル基又は炭素数１〜７のアルコキシ基のいずれか、Ｒ7は水素原子又は炭素数１〜６のアルキル基のいずれかを示す。）］
請求項１記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In general formula (1), L represents an organic group of formula (2) or formula (4), and in formula (2), W represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
X represents a hydrogen atom, a carboxyalkyl group having 2 to 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, a carbamoyl group, and a mono or dialkylcarbamoyl group having 2 to 7 carbon atoms. Group, amidino group, mono- or dialkylamidino group having 2 to 7 carbon atoms, acyl group having 1 to 8 carbon atoms, halogeno group, amino group, mono- or dialkylamino group having 1 to 6 carbon atoms, 4 to 6 carbon atoms Arylamino group, alkoxycarbonylamino group having 2 to 7 carbon atoms, aminoalkyl group having 1 to 3 carbon atoms, mono- or dialkylaminoalkyl group having 2 to 7 carbon atoms, N-alkyl-N- having 4 to 10 carbon atoms Alkoxycarbonylaminoalkyl group, piperidyloxy group, C7-10 iminoalkylpi Lysyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, pyrrolidyloxy group, C6-9 iminoalkylpyrrolidyloxy group, C7-13 alkoxycarbonylpyrrolidyloxy group, C2-2 7 hydroxycarbonylalkyl group, C3-C8 alkoxycarbonylalkyl group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, C4-C10 aryl group, carbon C6-C12 arylalkenyl group, C1-C10 alkoxy group, nitro group, trifluoromethyl group, C3-C8 alkyl group, C4-C10 arylsulfonyl group, C5-C12 Arylalkyl group, piperazine carbonyl group, iminoalkyl having 7 to 10 carbon atoms Piperazine carbonyl group, piperazine sulfonyl group, iminoalkylpiperazinesulfonyl group having 6 to 9 carbon atoms, benzylsulfonylamino group, piperidylalkyl group having 6 to 9 carbon atoms, iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms, carbon number 6 -9 piperididenealkyl group, 8-12 carbon iminoalkylpiperidenealkyl group, guanidino group, phosphono group, 2-9 carbon dialkoxyphosphoryl group, 1-4 carbon monoalkoxyhydroxyphosphoryl Groups, aminoethyloxy groups, C 3-6 dialkylaminosulfonyl groups, C 2-4 dialkylguanidino groups,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
Z represents a hydrogen atom, (12-2-1), or (12-3),
Figure 0004103147
(R 51 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 6 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 7 carbon atoms, and R 7 is a hydrogen atom or Any one of a C1-C6 alkyl group is shown.]]
The benzamidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 一般式（１）中、Ｌが式（２）の有機基を示す請求項１２記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 12, wherein L in the general formula (1) represents an organic group of the formula (2). 一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗが、水素原子又は炭素数１〜６のアルキル基を示し、
Ｘが、水素原子、炭素数２〜３のカルボキシアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、カルバモイル基、炭素数２〜７のモノもしくはジアルキルカルバモイル基、アミジノ基、炭素数２〜７のモノもしくはジアルキルアミジノ基、炭素数２〜８のアシル基、炭素数２〜６のジアルキルアミノ基、炭素数４〜６のアリールアミノ基、炭素数３〜７のジアルキルアミノアルキル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数４〜１０のアリール基、炭素数６〜１２のアリールアルケニル基、炭素数６〜１０のアルコキシ基、炭素数３〜８のアルキル基、炭素数４〜１０のアリールスルホニル基、炭素数７〜１０のイミノアルキルピペラジンカルボニル基、炭素数６〜９のイミノアルキルピペラジンスルホニル基、炭素数６〜９のピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数６〜９のピペリジデンアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基が挙げらる、請求項12記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In general formula (1), L represents an organic group of formula (2), and in formula (2), W represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
X represents a hydrogen atom, a carboxyalkyl group having 2 to 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent, and examples of the substituent include a carbamoyl group, a mono- or dialkylcarbamoyl group having 2 to 7 carbon atoms, an amidino group, a mono- or 2 to 7 carbon atoms Dialkylamidino group, acyl group having 2 to 8 carbon atoms, dialkylamino group having 2 to 6 carbon atoms, arylamino group having 4 to 6 carbon atoms, dialkylaminoalkyl group having 3 to 7 carbon atoms, piperidyloxy group, carbon number 7-10 iminoalkylpiperidyloxy group, pyrrolidyloxy group, C6-C9 iminoalkylpyrrolidyloxy group, C4-C10 aryl group, C6-C12 arylalkenyl group, C6-C6 -10 alkoxy group, C3-C8 alkyl group, C4-C10 arylsulfonyl group, charcoal C7-9 iminoalkylpiperazinecarbonyl group, C6-9 iminoalkylpiperazinesulfonyl group, C6-9 piperidylalkyl group, C8-12 iminoalkylpiperidylalkyl group, C6-9 13. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 12, which includes a piperididenealkyl group, an iminoalkylpiperidenealkyl group having 8 to 12 carbon atoms, and a guanidino group. 一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗは、水素原子又はメチル基を示し、Ｘが、水素原子、炭素数２〜３のカルボキシルアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、１−（ピリジル）−ピペリジン−４−カルボニル基又は置換基を有するベンゾイル基を示し、該置換基としては炭素数３〜７のジアルキルカルバモイル基、炭素数３〜７のジアルキルアミジノ基、ベンゾイル基、炭素数２〜６のジアルキルアミノ基、ピリジルアミノ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数６〜７のピリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジルアルキル基、炭素数８〜１２のイミノアルキルピペリジデンアルキル基、グアニジノ基、が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが水素原子、式（１２−２−１）を示す、請求項１２記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In general formula (1), L represents an organic group of formula (2), in formula (2), W represents a hydrogen atom or a methyl group, X represents a hydrogen atom, a C2-C3 carboxylalkyl. A group or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a 1- (pyridyl) -piperidine-4-carbonyl group or a benzoyl group having a substituent, and the substituent includes a dialkylcarbamoyl group having 3 to 7 carbon atoms, a dialkylamidino group having 3 to 7 carbon atoms, Benzoyl group, dialkylamino group having 2 to 6 carbon atoms, pyridylamino group, iminoalkylpiperidyloxy group having 7 to 10 carbon atoms, iminoalkylpyrrolidyloxy group having 6 to 9 carbon atoms, pyridylalkyl group having 6 to 7 carbon atoms , An iminoalkylpiperidylalkyl group having 8 to 12 carbon atoms, an iminoalkylpiperidenealkyl group having 8 to 12 carbon atoms, and a guanidino group,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 12, wherein Z represents a hydrogen atom, and represents the formula (12-2-1). 一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗは、水素原子を示し、Ｘが、水素原子、炭素数２〜３のカルボキシルアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、１−（４−ピリジル）−ピペリジン−４−カルボニル基又はパラ位に置換基を有するベンゾイル基を示し、該置換基としてはジメチルカルバモイル基、（ピロリジン−１−イル）カルボニル基、Ｎ，Ｎ−ジメチルアミジノ基、（ピロリジン−１−イル）（イミノ）メチル基、ベンゾイル基、１−ピロリジル基、４−ピリジルアミノ基、１−アセトイミドイル−４−ピペリジルオキシ基、４−ピリジルエチル基、グアニジノ基、が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが式（１２−２−１）を示す、請求項１２記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In general formula (1), L represents an organic group of formula (2), W in formula (2) represents a hydrogen atom, X represents a hydrogen atom, a C2-C3 carboxylalkyl group or carbon. Represents an alkoxycarbonylalkyl group of formula 3-6,
V represents a 1- (4-pyridyl) -piperidine-4-carbonyl group or a benzoyl group having a substituent at the para position, and the substituent includes a dimethylcarbamoyl group, a (pyrrolidin-1-yl) carbonyl group, N , N-dimethylamidino group, (pyrrolidin-1-yl) (imino) methyl group, benzoyl group, 1-pyrrolidyl group, 4-pyridylamino group, 1-acetimidoyl-4-piperidyloxy group, 4-pyridylethyl group , A guanidino group,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 12, wherein Z represents the formula (12-2-1). 一般式（１）中、Ｌが式（２）の有機基を示し、式（２）中、Ｗが、水素原子を示し、
Ｘが、炭素数２〜３のカルボキシアルキル基又は炭素数３〜６のアルコキシカルボニルアルキル基を示し、
Ｖが、メタ位又はパラ位に置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、炭素数２〜７のモノもしくはジアルキルアミジノ基、ピリジル基、カルボキシル基、アミジノ基、炭素数３〜６のジアルキルアミノカルボニル基、炭素数３〜６のジアルキルアミノスルホニル基、イミダゾリン−２−イル−アミノ基、ピロリジル基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが（１２-2-1）、（１２−３）のいずれかを示す、
Figure 0004103147
（Ｒ51は、水素原子または炭素数１〜６のアルキル基、Ｒ6は水素原子、炭素数１〜６のアルキル基又は炭素数１〜７のアルコキシ基のいずれか、Ｒ7は水素原子又は炭素数１〜６のアルキル基のいずれかを示す。）］
請求項１記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In general formula (1), L represents an organic group of formula (2), in formula (2), W represents a hydrogen atom,
X represents a carboxyalkyl group having 2 to 3 carbon atoms or an alkoxycarbonylalkyl group having 3 to 6 carbon atoms,
V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent at the meta position or para position, and the substituent includes a mono- or dialkylamidino group having 2 to 7 carbon atoms, a pyridyl group, a carboxyl group, an amidino group. A dialkylaminocarbonyl group having 3 to 6 carbon atoms, a dialkylaminosulfonyl group having 3 to 6 carbon atoms, an imidazolin-2-yl-amino group, a pyrrolidyl group, a piperidyloxy group, and an iminoalkylpiperidyloxy group having 7 to 10 carbon atoms. Are mentioned,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
Z represents either (12-2-1) or (12-3),
Figure 0004103147
(R 51 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R 6 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 7 carbon atoms, and R 7 is a hydrogen atom or Any one of a C1-C6 alkyl group is shown.]]
The benzamidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 一般式（１）中、Ｚが２−アセトアミド−２−エトキシカルボニルエテニル基、２−アセトアミド−２−メトキシカルボニルエテニル基、２−アセトアミド−２−カルボキシルエテニル基、又は２−カルボキシ−２−オキソエチル基のいずれかである請求項17記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In general formula (1), Z represents a 2-acetamido-2-ethoxycarbonylethenyl group, 2-acetamido-2-methoxycarbonylethenyl group, 2-acetamido-2-carboxylethenyl group, or 2-carboxy-2 18. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 17, which is any one of -oxoethyl groups. 一般式（１）中、Ｘがエトキシカルボニルメチル基又はカルボキシメチル基のいずれかである請求項17記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。18. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 17, wherein X in the general formula (1) is either an ethoxycarbonylmethyl group or a carboxymethyl group. 一般式（１）中、Ｖが、パラ位に置換基を有するベンゾイル、ピリジンカルボニルもしくはピペリジンカルボニル基を示し、該置換基としては、アミジノ基、カルボキシル基、ジメチルアミノカルボニル基、１−ピロリジルカルボニル基、４−ピペリジルオキシ基又は１−アセトイミドイル−４−ピペリジルオキシ基のいずれかである請求項17記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In the general formula (1), V represents a benzoyl, pyridinecarbonyl or piperidinecarbonyl group having a substituent at the para position. Examples of the substituent include an amidino group, a carboxyl group, a dimethylaminocarbonyl group, and 1-pyrrolidylcarbonyl. 18. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 17, which is any one of a group, 4-piperidyloxy group and 1-acetimidoyl-4-piperidyloxy group. 一般式（１）中、Ｌが式（２）有機基を示し、
Ｗが、水素原子を示し、
Ｘが、置換基を有するベンジル基を示し、置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基、アミジノ基、ベンジルオキシカルボニル基、ヒドロキシ基、ハロゲノ基、アミジノピペリジルオキシ基もしくは炭素数１〜３のアルキル基があげられ、
Ｖが、水素原子、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチル、インドールカルボニル、フェニルチオカルボニル、ピリジンカルボニル、ピペリジンカルボニル基もしくはベンズイミドイル基または置換基を有していてもよい炭素数１〜６のアルカンスルホニル、ベンゼンスルホニル基を示し、置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数２〜７のヒドロキシカルボニルアルキル基、炭素数３〜８のアルコキシカルボニルアルキル基、炭素数３〜７のヒドロキシカルボニルアルケニル基、炭素数４〜８のアルコキシカルボニルアルケニル基、ホスホノ基、炭素数２〜９のジアルコキシホスホリル基、炭素数１〜４のモノアルコキシヒドロキシホスホリル基が挙げられ、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが水素原子、炭素数１〜６のアルキル基、ハロゲノ基または式（１２−１）、（１２−２）、（１２−３）のいずれかを示す、請求項１記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。In general formula (1), L represents an organic group of formula (2),
W represents a hydrogen atom,
X represents a benzyl group having a substituent, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, and 7 to 10 carbon atoms. Iminoalkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, C6-8 piperidylalkyl group, C8-11 iminoalkylpiperidylalkyl group, C9-15 alkoxycarbonylpiperidyl group Alkyl group, pyrrolidyloxy group, iminoalkylpyrrolidyloxy group having 6 to 9 carbon atoms, alkoxycarbonylpyrrolidyloxy group having 7 to 13 carbon atoms, amidino group, benzyloxycarbonyl group, hydroxy group, halogeno group, amidinopiperidyl Oxy group or C1-C3 alkyl Group, and the like,
V is a hydrogen atom, 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinylamylacetyl, indolecarbonyl, phenylthiocarbonyl, pyridinecarbonyl, piperidinecarbonyl group or A benzimidoyl group or an optionally substituted alkanesulfonyl or benzenesulfonyl group having 1 to 6 carbon atoms is shown, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, and 2 to 7 carbon atoms. Hydroxycarbonylalkyl group, C3-C8 alkoxycarbonylalkyl group, C3-C7 hydroxycarbonylalkenyl group, C4-C8 alkoxycarbonylalkenyl group, phosphono group, C2-C9 Alkoxy phosphoryl groups include monoalkoxy hydroxy phosphoryl group having 1 to 4 carbon atoms,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
The benzamidine derivative according to claim 1, wherein Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, or any one of formulas (12-1), (12-2), and (12-3). A pharmaceutically acceptable salt. Ｘが、置換基を有するベンジル基を示し、置換基としては、カルボキシル基、炭素数２〜７のアルコキシカルボニル基、炭素数１〜６のアルキルスルホニルオキシ基、ピペリジルオキシ基、炭素数７〜１０のイミノアルキルピペリジルオキシ基、炭素数８〜１４のアルコキシカルボニルピペリジルオキシ基、炭素数６〜８のピペリジルアルキル基、炭素数８〜１１のイミノアルキルピペリジルアルキル基、炭素数９〜１５のアルコキシカルボニルピペリジルアルキル基、ピロリジルオキシ基、炭素数６〜９のイミノアルキルピロリジルオキシ基、炭素数７〜１３のアルコキシカルボニルピロリジルオキシ基があげられ、
Ｖが、水素原子、ベンゼンスルホニル、２−ナフタレンスルホニル、カンファースルホニル、シンナモイル、ピペリジンカルボニル、フェニルアセチル、キヌクリジニルアミノアセチル、キヌクリジニウミルアセチルまたは炭素数１〜６のアルカンスルホニル基を示し、
Ｙが式（７）を示し、式（７）中、ｎは１の整数を示し、
Ｚが水素原子または式（１２−１）のいずれかを示す、請求項21記載のベンズアミジン誘導体又はその医薬的に許容しうる塩。X represents a benzyl group having a substituent, and examples of the substituent include a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an alkylsulfonyloxy group having 1 to 6 carbon atoms, a piperidyloxy group, and 7 to 10 carbon atoms. Iminoalkylpiperidyloxy group, C8-14 alkoxycarbonylpiperidyloxy group, C6-8 piperidylalkyl group, C8-11 iminoalkylpiperidylalkyl group, C9-15 alkoxycarbonylpiperidyl group An alkyl group, a pyrrolidyloxy group, an iminoalkylpyrrolidyloxy group having 6 to 9 carbon atoms, and an alkoxycarbonylpyrrolidyloxy group having 7 to 13 carbon atoms,
V represents a hydrogen atom, benzenesulfonyl, 2-naphthalenesulfonyl, camphorsulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, quinuclidinylaminoacetyl, quinuclidinyl acetyl, or an alkanesulfonyl group having 1 to 6 carbon atoms. ,
Y represents Formula (7), and in Formula (7), n represents an integer of 1,
22. The benzamidine derivative or a pharmaceutically acceptable salt thereof according to claim 21, wherein Z represents either a hydrogen atom or formula (12-1). （３Ｒ）−３−（４−アミジノベンゾイルアミノ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−（４−ジメチルカルバモイルベンゾイルアミノ）ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−（４−カルボキシルベンゾイルアミノ）ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−カルボニル）ベンゾイルアミノ］ブタン酸、（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（１−（１−イミノエチル）ピペリジル−４−オキシ）ベンゾイルアミノ］ブタン酸又は（３Ｒ）−４−［５−アミジノ−２−（２−カルボキシ−２−オキソエチル）フェノキシ］−３−［４−（ピロリジン−１−スルホニル）ベンゾイルアミノ］ブタン酸よりなる群の中から選ばれるベンズアミジン誘導体又はその医薬的に許容しうる塩。(3R) -3- (4-amidinobenzoylamino) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] butanoic acid, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- (4-dimethylcarbamoylbenzoylamino) butanoic acid, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy]- 3- (4-carboxylbenzoylamino) butanoic acid, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-carbonyl) benzoyl Amino] butanoic acid, (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (1- (1-i Noethyl) piperidyl-4-oxy) benzoylamino] butanoic acid or (3R) -4- [5-amidino-2- (2-carboxy-2-oxoethyl) phenoxy] -3- [4- (pyrrolidine-1-sulfonyl) Benzoylamino] benzamidine derivatives selected from the group consisting of butanoic acid or pharmaceutically acceptable salts thereof. 請求項１記載のベンズアミジン誘導体またはその塩を有効成分として含有する抗血液凝固剤または血栓もしくは塞栓の予防・治療剤。An anticoagulant or a prophylactic / therapeutic agent for thrombosis or embolism comprising the benzamidine derivative or salt thereof according to claim 1 as an active ingredient. 請求項23記載のベンズアミジン誘導体またはその塩を有効成分として含有する抗血液凝固剤または血栓もしくは塞栓の予防・治療剤。24. An anticoagulant or a prophylactic / therapeutic agent for thrombosis or embolism containing the benzamidine derivative or a salt thereof according to claim 23 as an active ingredient.
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